Abstract Background Type 1 diabetes mellitus (T1DM), an autoimmune disease with a genetic tendency, has an increasing prevalence. Long non-coding RNA (lncRNA) and circular RNA (circRNA) are receiving increasing attention in disease pathogenesis. However, their roles in T1DM are poorly understood. The present study aimed at identifying signature lncRNAs and circRNAs and investigating their roles in T1DM using the competing endogenous RNA (ceRNA) network analysis. Methods The T1DM expression profile was downloaded from Gene Expression Omnibus (GEO) database to identify the differentially expressed circRNAs, lncRNAs, and mRNAs. The biological functions of these differentially expressed circRNAs, lncRNAs, and mRNAs were analyzed by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Targeting relationships of circRNA-miRNA, lncRNA-miRNA, and miRNA-mRNA were predicted, and the circRNA-lncRNA-miRNA-mRNA ceRNA regulatory network was established. Finally, qRT-PCR was applied to identify the effect of hsa_circ_0002202 inhibition on the IFN-I induced macrophage inflammation. Results A total of 178 circRNAs, 404 lncRNAs, and 73 mRNAs were identified to be abnormally expressed in T1DM samples. Functional enrichment analysis results indicated that the differentially expressed genes were mainly enriched in extracellular matrix components and macrophage activation. CeRNA regulatory network showed that circRNAs and lncRNAs regulate mRNAs through integrate multiple miRNAs. In addition, in vitro experiments showed that hsa_circ_0002202 inhibition suppressed the type I interferon (IFN-I)-induced macrophage inflammation. Conclusion In the present study, the circRNA-lncRNA-miRNA-mRNA ceRNA regulatory network in T1DM was established for the first time. We also found that hsa_circ_0002202 inhibition suppressed the IFN-I-induced macrophage inflammation. Our study may lay a foundation for future studies on the ceRNA regulatory network in T1DM. Keywords: type 1 diabetes mellitus, ceRNA network, peripheral blood mononuclear cell, macrophage Introduction Type 1 diabetes mellitus (T1DM), also known as insulin-dependent diabetes mellitus, is a chronic autoimmune disease characterized by impaired islet function and decreased insulin secretion.[28]^1^,[29]^2 The cause of T1DM involves various factors, including epigenetic, individual genetics, and environmental triggers.[30]^3–6 T1DM is diagnosed at all ages.[31]^7^,[32]^8 Among them, approximately 78,000 young people are diagnosed with T1DM annually worldwide.[33]^9 Moreover, recent studies revealed that the incidence of T1DM is on the rise at the age of 10–14, and the number of children and adolescents with T1DM worldwide is estimated to continue to increase.[34]^10^,[35]^11 Patients with T1DM usually suffer from the disease for a longer time, which requires them to inject insulin daily and perform continuous blood glucose monitoring, resulting in huge lifetime costs and time requirements.[36]^12 At the same time, T1DM has serious complications such as ketoacidosis, heart disease, stroke, kidney failure, and blindness.[37]^13–17 These long-term effects are likely to spread to other areas of the patients’ lives, which will cause economic impact and social burdens.[38]^12^,[39]^18 Thus, it is necessary to diagnose T1DM early. However, the traditional diagnostic methods of diabetes are no longer satisfactory.[40]^19 Therefore, it is urgent to understand the etiology and pathogenesis of T1DM for more effective diagnosis and treatment. Through the recent researches on the post-transcriptional regulatory mechanism, non-coding RNA (ncRNA), which does not have traditional RNA functions in protein translation, was discovered.[41]^20 Among them, the long non-coding RNA (lncRNA) is a kind of linear non-coding RNA with a length of more than 200 nucleotides,[42]^21 and circular RNA (circRNA) is a kind of endogenous non-coding RNA with a closed-loop structure.[43]^22 Previous studies have shown the vital roles of various lncRNAs and circRNAs in T1DM. lncRNA Lnc13 is up-regulated in β-cells and contributes to the pathogenesis of T1DM by increasing pancreatic β-cell inflammation.[44]^23 Ding et al reported that lncRNA MALAT1 induces the dysfunction of β-cells in T1DM.[45]^24 Another study by Zhang et al found that circRNA circPPM1F modulates M1 macrophage activation and pancreatic islet inflammation in T1DM.[46]^25 Therefore, examining the expression of lncRNAs and circRNAs and exploring their underlying mechanism in T1DM opens avenues to a better understanding of the T1DM pathogenesis. Both lncRNA and circRNA can act as microRNA (miRNA) sponges to compete with the same corresponding miRNA response element (MRE), thus controlling subsequent miRNA post-transcriptional regulation and forming competitive endogenous RNA (ceRNA) regulatory network.[47]^26–28 The ceRNA regulatory networks in diabetes have been widely reported.[48]^29–32 While in T1DM, few studies regarding the ceRNA regulatory network were reported. Li et al and Luo et al identified the circRNA-miRNA-mRNA network in T1DM via bioinformatic analysis.[49]^22^,[50]^33 Shi et al reported the lncRNA-miRNA-mRNA regulatory networks in T1DM.[51]^34 Thus, further studies aimed at clarifying ceRNA-based molecular mechanisms in T1DM are needed to provide potential opportunities for better understanding the pathogenesis and treatment of T1DM. With the popularization of high-throughput sequencing, bioinformatics analysis has been widely used in multiple disease research. Researchers can analyze data from various public databases and explore the regulatory mechanism underlying the disease. Here, we identified the differentially expressed circRNAs (DEcircRNAs), lncRNAs (DElncRNAs), mRNAs (DEmRNAs) in T1DM using expression profile [52]GSE133225 and [53]GSE133217 downloaded from the Gene Expression Omnibus (GEO) database.[54]^35 Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to detect the function of these differentially expressed genes. Then, the circRNA-miRNA, lncRNA-miRNA, and miRNA-mRNA interaction were predicted, and the circRNA-lncRNA-miRNA-mRNA ceRNA regulatory network was constructed. This is the first time to construct the ceRNA regulatory network by comprehensive screening of circRNA, lncRNA, miRNA, and mRNA in T1DM. Materials and Methods Data Sources Two individual cohorts from the GEO database ([55]http://www.ncbi.nlm.nih.gov/geo/) were included in this study. One is the circRNA, lncRNA, and mRNA expression profile [56]GSE133225, and the other one is the miRNA expression profile [57]GSE133217. Both expression profiles were provided by Zhang Caiyan and Zhou Yufeng,[58]^25^,[59]^36 and included 4 peripheral blood mononuclear cells (PBMCs) samples from T1DM patients and 4 PBMCs samples from healthy volunteers. Summary of Statistical Analysis In the current study, we first analyzed the circRNA, lncRNA, miRNA, and mRNA expression using the microarray [60]GSE133225 and [61]GSE133217. Next, according to the filtrate threshold (P value < 0.05 and log2 (fold change) > 1), the differentially expressed circRNA, lncRNA, and mRNA were screened out. GO and KEGG enrichment analyses were performed to better comprehend the mechanisms of T1DM. Then, the target prediction was performed with the online web tools Circinteractome, LncBase, and starBase, and the circRNA-lncRNA-miRNA-mRNA interaction network was established. Finally, circRNA hsa_circ_0002202 was selected for further verification. A brief workflow was shown in [62]Figure 1. Figure 1. [63]Figure 1 [64]Open in a new tab The analysis flow chart of this study. Differential Expression Analysis R software (Ver. 3.5.0, [65]https://www.r-project.org/) was employed for microarray analysis. The “affy” package was used for normalizing microarray expression profiles as described before.[66]^37 Then, empirical Bayes moderated t-test in the “limma” package[67]^38 was applied to screen the differentially expressed genes (DEGs) between T1DM samples and normal samples with P value < 0.05 and log2 (fold change) > 1 as the threshold. The code for the differential expression analysis was shown in [68]Supplementary File 1. Functional and Pathway Enrichment Analysis of Differentially Expressed circRNAs, lncRNAs, and mRNAs To better comprehend the mechanisms of T1DM, GO ([69]http://www.geneontology.org/) analysis and KEGG ([70]http://www.kegg.jp/) pathway analysis of the differentially expressed circRNA, lncRNA, and mRNAs was conducted with the “clusterProfiler” package[71]^39 using P < 0.05 (adjusted using Benjamin and Hochberg method) as the threshold. Specifically, GO analysis is used to construct gene annotation base on biological processes (BP, a biological objective to which the gene or gene product contributes), cellular components (CC, the place in the cell where a gene product is active), and molecular functions (MF, the biochemical activity (including specific binding to ligands or structures) of a gene product),[72]^40 and KEGG analysis is used to interpret the potential functions and pathways.[73]^41 The code for the enrichment analysis was shown in [74]Supplementary File 2. For the enrichment analysis for differentially expressed circRNAs, we used their parental genes. For the enrichment analysis for differentially expressed lncRNAs, we used their associated genes. Construction of circRNA-lncRNA-miRNA-mRNA ceRNA Regulatory Network The expression correlation of differentially expressed circRNAs, lncRNAs, and mRNAs was calculated using Pearson correlation coefficients with the “psych” package ([75]https://cran.r-project.org/web/packages/psych/). The code for the correlation analysis was shown in [76]Supplementary File 3. circRNA-mRNA and lncRNA-mRNA with r > 0.7 and P < 0.05 were selected for further study. Then, the Circinteractome web tool ([77]https://circinteractome.nia.nih.gov/) was applied to predict the circRNA-miRNA interactions. LncBase web tool ([78]http://carolina.imis.athena-innovation.gr/diana_tools/web/index.ph p?r=lncbasev2/index) was applied to predict the lncRNA-miRNA interactions. starBase web tool ([79]http://starbase.sysu.edu.cn/) was applied to predict the miRNA-mRNA interactions. Finally, a circRNA-lncRNA-miRNA-mRNA interaction network visualized by Cytoscape software[80]^42 based on the ceRNA theory. Cell Culture and Treatment Human THP-1 cell line from Procell Life Science&Technology Co., Ltd. (Wuhan, China) was cultured in the RPMI-1640 medium supplied with 10% fetal bovine serum (FBS, Gibco, Gaithersburg, MD, USA) and 1% penicillin-streptomycin (Gibco) at 37°C with 5% CO[2]. Then, according to a previous study,[81]^36 THP-1-derived macrophages were induced by treating with 50 ng/mL phorbol 12-myristate 13-acetate (PMA) for 48 h. Cell transfection was performed using Lipofectamine 3000 reagent (Invitrogen, USA) with the chemically synthesized circRNA small interfering RNAs (si-circ, sequence: 5ʹ-AGTACAACAATTCAGGTGATT-3ʹ), and small interfering RNAs negative control (si-NC, sequence: 5ʹ-UUCUCCGAACGUGUCACGUTT-3ʹ). After 48 h of transfection, the macrophages were treated with type I interferon (IFN-I, 1000 units/mL, PBL Assay Science, USA) to induce the inflammation. Quantitative Real-Time PCR (qRT-PCR) Total RNA was extracted from cells with Trizol (Invitrogen, USA). Next, cDNA was reverse transcribed with PrimeScript First Strand cDNA Synthesis Kit (Takara, Japan). Then, the qRT-PCR reaction was performed with SYBR^® Premix Ex Taq™ II (Takara, Japan) on the LightCycler 96 PCR system (Roche, Rotkreuz, Switzerland). β-actin was selected as the internal control according to the geNorm[82]^43 and normFinder[83]^44 algorithms. The level of RNA was quantified by the 2^−ΔΔCT method. Primers were displayed in [84]Table 1. Table 1. Primers Used for qRT-PCR Name Sequence (5’-3’) IFIT1 forward GCCTTGCTGAAGTGTGGAGGAA IFIT1 reverse ATCCAGGCGATAGGCAGAGATC IFIH1 forward GACTCGGGAATTCGTGGAGG IFIH1 reverse CTCAAACGATGGAGAGGGCA iNOS forward GCTCTACACCTCCAATGTGACC iNOS reverse CTGCCGAGATTTGAGCCTCATG CXCL10 forward GGTGAGAAGAGATGTCTGAATCC CXCL10 reverse GTCCATCCTTGGAAGCACTGCA hsa_circ_0002202 forward GACAAAAGCATGGGGTGTGAG hsa_circ_0002202 reverse GCCTCTTCCCATCACCTGAAT GAPDH forward GTCTCCTCTGACTTCAACAGCG GAPDH reverse ACCACCCTGTTGCTGTAGCCAA 18S rRNA forward ACACGGACAGGATTGACAGA 18S rRNA reverse GGACATCTAAGGGCATCACA β-actin forward CACCATTGGCAATGAGCGGTTC β-actin reverse AGGTCTTTGCGGATGTCCACGT β-tubulin forward TGGACTCTGTTCGCTCAGGT β-tubulin reverse TGCCTCCTTCCGTACCACAT U6 forward CTCGCTTCGGCAGCACA U6 reverse AACGCTTCACGAATTTGCGT [85]Open in a new tab Nuclear and Cytoplasmic Separation In brief, nuclear and cytoplasmic RNAs were extracted using the PARIS kit (Invitrogen, Carlsbad, CA, USA). Then, the RNA extractions were subjected to qRT-PCR. U6 was used as the internal control of the nucleus, and 18S rRNA was used as the internal control of the cytoplasm. Statistical Analysis The qRT-PCR experiments were performed in triplicate, and the results were shown as mean ± SD. Statistical difference was analyzed using one-way ANOVA with GraphPad Prism (Ver. 8.0, GraphPad Software, Inc). P < 0.05 was considered to be statistically significant. Results Identification of Differentially Expressed circRNA in T1DM and Healthy Patients By analyzing the circRNA expression in microarray [86]GSE133225 ([87]Figure 2A and [88]B), we identified 178 differentially expressed circRNAs (DEcircRNAs, 77 up-regulated and 101 down-regulated) ([89]Table 2). We also analyzed the chromosomal positions of these DEcircRNAs, and the top 5 chromosomes are as follows: chr1 (18, 10.11%), chr2 (15, 8.43%), chr3 (12, 6.74%), chr7 (12, 6.74) %), chr10 (11, 6.18%). Functional enrichment analysis of DEcircRNAs was performed using the “clusterProfiler” tool. The results showed that the most significantly enriched GO terms were related to collagen fibril organization (GO: 0030199), membrane raft (GO: 0045121), and extracellular matrix structural constituent conferring tensile strength (GO: 0030020) ([90]Figure 2C and [91]Table 3). For the KEGG pathway analysis, the DEcircRNAs were enriched in protein digestion and absorption (hsa04974) ([92]Table 4). Figure 2. [93]Figure 2 [94]Open in a new tab The differentially expressed circRNAs in T1DM and healthy patients. (A) Volcano plot of DEcircRNAs between normal and T1DM groups. Red and green indicate up- and downregulation, respectively. (B) Heatmap of DEcircRNAs between normal and T1DM groups. Red color represents increased expression, and green color represents decreased expression. The darker the color, the greater the difference of circRNA expression. (C) Enrichment analysis of the DEcircRNAs in the categories biological process, cellular component, and molecular function. Table 2. Differentially Expressed circRNAs Between the Control Group and T1DM Group circRNAs Log2FoldChange Regulation P-value P-adj hsa_circ_0060875 −2.1258337 Down 9.90×10^−5 0.36011603 hsa_circ_0091120 −1.8790129 Down 0.00502998 0.61872814 hsa_circ_0018219 −1.8216577 Down 0.03718813 0.6896574 hsa_circ_0083266 −1.8178634 Down 0.01012685 0.6404092 hsa_circ_0081949 −1.7877271 Down 0.04837352 0.69864211 hsa_circ_0017702 −1.7544417 Down 0.00777686 0.6371225 hsa_circ_0089817 −1.7206724 Down 0.00023941 0.36707996 hsa_circ_0061761 −1.6617103 Down 0.03278591 0.6886992 hsa_circ_0043949 −1.6515359 Down 0.00163728 0.49940512 hsa_circ_0026805 −1.6448912 Down 0.03133761 0.6886992 hsa_circ_0066856 −1.5895376 Down 0.00030271 0.36707996 hsa_circ_0010600 −1.5588221 Down 0.00021508 0.36707996 hsa_circ_0089863 −1.5576906 Down 0.00085911 0.45375667 hsa_circ_0012945 −1.5426338 Down 0.00031327 0.36707996 hsa_circ_0087118 −1.5293394 Down 0.01309075 0.6461669 hsa_circ_0025477 −1.5269283 Down 2.49×10^−5 0.27197545 hsa_circ_0035318 −1.4846081 Down 0.02228095 0.67318317 hsa_circ_0011345 −1.4808367 Down 0.00116665 0.47332912 hsa_circ_0029046 −1.4680823 Down 1.66×10^−5 0.27136735 hsa_circ_0070052 −1.4551817 Down 0.00043961 0.37883821 hsa_circ_0055707 −1.4461302 Down 0.01391048 0.6461669 hsa_circ_0018927 −1.4141948 Down 0.0203531 0.66888734 hsa_circ_0053289 −1.3992471 Down 0.00139236 0.49940512 hsa_circ_0055713 −1.3964991 Down 0.01169841 0.6461669 hsa_circ_0092322 −1.3886845 Down 1.32×10^−5 0.27136735 hsa_circ_0045848 −1.3854297 Down 0.04413029 0.69594076 hsa_circ_0069584 −1.3853501 Down 0.01824692 0.65662851 hsa_circ_0008441 −1.3733694 Down 0.00074912 0.44105722 hsa_circ_0073007 −1.3518705 Down 0.04300145 0.69594076 hsa_circ_0030977 −1.3421675 Down 0.03991266 0.69072451 hsa_circ_0088254 −1.3367378 Down 0.00795582 0.63723776 hsa_circ_0012093 −1.312721 Down 0.03432713 0.6886992 hsa_circ_0034676 −1.3119179 Down 0.0072544 0.6371225 hsa_circ_0082293 −1.2977776 Down 0.00872193 0.63723776 hsa_circ_0080325 −1.2957511 Down 0.0029555 0.52887377 hsa_circ_0004712 −1.2890482 Down 0.01102659 0.6461669 hsa_circ_0068381 −1.270335 Down 0.01699615 0.65626057 hsa_circ_0042502 −1.2651427 Down 0.03467318 0.6886992 hsa_circ_0025413 −1.2635234 Down 0.0184742 0.6573827 hsa_circ_0068488 −1.2544915 Down 0.02684532 0.6886992 hsa_circ_0072670 −1.24989 Down 0.00188517 0.52606124 hsa_circ_0078706 −1.2409986 Down 0.02179647 0.67318317 hsa_circ_0025473 −1.2401025 Down 0.00671056 0.6371225 hsa_circ_0080593 −1.2388893 Down 0.0129599 0.6461669 hsa_circ_0082426 −1.236374 Down 0.02682174 0.6886992 hsa_circ_0002456 −1.2308499 Down 0.0340347 0.6886992 hsa_circ_0035624 −1.229398 Down 0.01432306 0.6461669 hsa_circ_0027593 −1.2143428 Down 0.01510762 0.6461669 hsa_circ_0033522 −1.2109569 Down 0.00530799 0.61994831 hsa_circ_0070813 −1.2004595 Down 0.04540634 0.69594076 hsa_circ_0089089 −1.197761 Down 0.03000448 0.6886992 hsa_circ_0008732 −1.1974429 Down 0.0014563 0.49940512 hsa_circ_0083243 −1.1873178 Down 0.00020845 0.36707996 hsa_circ_0044570 −1.1776689 Down 0.00506876 0.61872814 hsa_circ_0051957 −1.1766531 Down 0.0188451 0.66175152 hsa_circ_0007872 −1.1753034 Down 0.00571746 0.6277625 hsa_circ_0003146 −1.1698955 Down 0.03610804 0.6896574 hsa_circ_0088267 −1.1654894 Down 0.0060454 0.62927103 hsa_circ_0020296 −1.1650009 Down 0.00111814 0.47332912 hsa_circ_0012285 −1.153328 Down 0.00205924 0.52606124 hsa_circ_0086765 −1.1459122 Down 0.00525476 0.61994831 hsa_circ_0084641 −1.1433833 Down 0.01349551 0.6461669 hsa_circ_0015060 −1.1429878 Down 0.00053871 0.41025776 hsa_circ_0065173 −1.1388487 Down 0.00755684 0.6371225 hsa_circ_0043616 −1.1332645 Down 0.03696064 0.6896574 hsa_circ_0047903 −1.1276276 Down 0.01716979 0.65626057 hsa_circ_0018827 −1.1202055 Down 0.00018818 0.36707996 hsa_circ_0015069 −1.1175352 Down 0.04417262 0.69594076 hsa_circ_0032813 −1.1131832 Down 0.00855541 0.63723776 hsa_circ_0019143 −1.112285 Down 0.04029593 0.69072451 hsa_circ_0008537 −1.1053958 Down 0.00053611 0.41025776 hsa_circ_0002529 −1.1048341 Down 0.01225173 0.6461669 hsa_circ_0046840 −1.0988722 Down 0.00035777 0.36707996 hsa_circ_0028284 −1.0905105 Down 0.04120974 0.69432323 hsa_circ_0019432 −1.0752782 Down 0.00295458 0.52887377 hsa_circ_0047303 −1.0705012 Down 0.00689965 0.6371225 hsa_circ_0072137 −1.0684678 Down 0.01800286 0.65626057 hsa_circ_0024130 −1.0663774 Down 0.0205363 0.6691564 hsa_circ_0022919 −1.0578978 Down 0.0093951 0.63723776 hsa_circ_0022238 −1.0545557 Down 0.02150931 0.67318317 hsa_circ_0086805 −1.0531799 Down 0.01662828 0.65471981 hsa_circ_0077069 −1.0513113 Down 0.02550238 0.68798091 hsa_circ_0057374 −1.0509624 Down 0.00039234 0.36707996 hsa_circ_0069321 −1.0491406 Down 0.00507185 0.61872814 hsa_circ_0007471 −1.0383975 Down 0.01103246 0.6461669 hsa_circ_0032858 −1.0382432 Down 0.00588311 0.62927103 hsa_circ_0033892 −1.0300829 Down 0.04042024 0.69072451 hsa_circ_0024575 −1.023773 Down 0.04526006 0.69594076 hsa_circ_0083836 −1.0232697 Down 0.00482139 0.60677969 hsa_circ_0064419 −1.0230977 Down 0.00012256 0.3648499 hsa_circ_0030657 −1.0226422 Down 0.00883236 0.63723776 hsa_circ_0087729 −1.0196745 Down 0.03005932 0.6886992 hsa_circ_0020964 −1.0153533 Down 0.02651006 0.6886992 hsa_circ_0078325 −1.0146273 Down 0.0142381 0.6461669 hsa_circ_0068030 −1.0135546 Down 0.00881102 0.63723776 hsa_circ_0087884 −1.0107733 Down 0.02874001 0.6886992 hsa_circ_0067127 −1.0102228 Down 0.03491637 0.6886992 hsa_circ_0077292 −1.0098441 Down 0.03166391 0.6886992 hsa_circ_0050829 −1.0079665 Down 0.00046365 0.38552675 hsa_circ_0088545 −1.0038141 Down 0.02816448 0.6886992 hsa_circ_0066559 −1.0001944 Down 0.00562765 0.62317278 hsa_circ_0030691 1.00075362 Up 0.03650781 0.6896574 hsa_circ_0073355 1.00406779 Up 0.01584992 0.65471981 hsa_circ_0060973 1.00552219 Up 0.01129814 0.6461669 hsa_circ_0071490 1.00837299 Up 0.02198034 0.67318317 hsa_circ_0073332 1.01653192 Up 0.00029189 0.36707996 hsa_circ_0041267 1.02731163 Up 0.04826044 0.69864211 hsa_circ_0034557 1.02903097 Up 0.04566388 0.69594076 hsa_circ_0014206 1.03151729 Up 0.00754327 0.6371225 hsa_circ_0034188 1.03292459 Up 7.23×10^−5 0.36011603 hsa_circ_0084862 1.04447426 Up 0.03297313 0.6886992 hsa_circ_0043575 1.04451466 Up 0.00606669 0.62927103 hsa_circ_0066752 1.05303312 Up 0.00123282 0.48639953 hsa_circ_0018918 1.05369965 Up 0.03867368 0.6896574 hsa_circ_0030816 1.06017092 Up 0.01231415 0.6461669 hsa_circ_0002308 1.06451001 Up 0.00139462 0.49940512 hsa_circ_0057940 1.06723667 Up 0.0355786 0.6886992 hsa_circ_0084763 1.06852044 Up 0.0121094 0.6461669 hsa_circ_0079554 1.06923574 Up 0.02296689 0.67670006 hsa_circ_0003310 1.07580527 Up 0.03868275 0.6896574 hsa_circ_0072445 1.0780832 Up 0.01833869 0.6573827 hsa_circ_0004607 1.09052865 Up 0.0026797 0.52887377 hsa_circ_0074026 1.10437363 Up 0.00887386 0.63723776 hsa_circ_0013280 1.11294406 Up 0.02142065 0.67318317 hsa_circ_0000324 1.11328742 Up 0.02004466 0.6663805 hsa_circ_0011437 1.11571417 Up 0.00203065 0.52606124 hsa_circ_0038162 1.12089009 Up 0.0312031 0.6886992 hsa_circ_0006561 1.12140856 Up 0.02905904 0.6886992 hsa_circ_0019321 1.12534202 Up 0.01003317 0.6404092 hsa_circ_0066588 1.13259964 Up 0.00644124 0.6371225 hsa_circ_0068846 1.13350867 Up 0.04980974 0.69965823 hsa_circ_0048941 1.13392642 Up 0.00783921 0.6371225 hsa_circ_0013276 1.1353225 Up 0.01594875 0.65471981 hsa_circ_0084803 1.13561704 Up 0.00291642 0.52887377 hsa_circ_0009718 1.14501876 Up 0.00113062 0.47332912 hsa_circ_0052890 1.14899657 Up 0.00110269 0.47332912 hsa_circ_0052578 1.15746251 Up 0.00204063 0.52606124 hsa_circ_0004247 1.16577189 Up 0.03834653 0.6896574 hsa_circ_0006366 1.17060861 Up 0.02336843 0.67886043 hsa_circ_0004970 1.17164435 Up 0.00191073 0.52606124 hsa_circ_0003760 1.19544727 Up 0.00830217 0.63723776 hsa_circ_0077040 1.19660605 Up 0.00038828 0.36707996 hsa_circ_0064649 1.20323629 Up 0.00634396 0.63530743 hsa_circ_0057921 1.22298163 Up 0.00658344 0.6371225 hsa_circ_0010167 1.22782484 Up 0.01705561 0.65626057 hsa_circ_0002626 1.23796418 Up 0.04850693 0.69864211 hsa_circ_0004814 1.24697128 Up 0.01902014 0.66175152 hsa_circ_0073356 1.24865998 Up 0.0053345 0.61994831 hsa_circ_0045123 1.24884849 Up 0.02550036 0.68798091 hsa_circ_0069213 1.25118583 Up 0.00366065 0.58881715 hsa_circ_0079548 1.25190508 Up 0.01484117 0.6461669 hsa_circ_0090098 1.25536841 Up 0.02596742 0.6886992 hsa_circ_0030624 1.25599738 Up 0.03651889 0.6896574 hsa_circ_0069324 1.26605445 Up 0.00060556 0.42191899 hsa_circ_0060335 1.28618107 Up 0.00081571 0.44105722 hsa_circ_0058206 1.33626161 Up 0.01802886 0.65626057 hsa_circ_0056882 1.34999287 Up 0.03545574 0.6886992 hsa_circ_0013437 1.36836499 Up 0.01654656 0.65471981 hsa_circ_0046700 1.36944609 Up 0.0439923 0.69594076 hsa_circ_0082549 1.37107512 Up 9.10×10^−5 0.36011603 hsa_circ_0057436 1.37990777 Up 0.00097797 0.47332912 hsa_circ_0048871 1.42092532 Up 0.04047976 0.69077151 hsa_circ_0009443 1.48425272 Up 0.00287515 0.52887377 hsa_circ_0060450 1.51788173 Up 0.01218226 0.6461669 hsa_circ_0060456 1.55691545 Up 0.04257115 0.69594076 hsa_circ_0026352 1.61091952 Up 0.0312629 0.6886992 hsa_circ_0056621 1.65069395 Up 0.01137625 0.6461669 hsa_circ_0057880 1.65520964 Up 0.01050849 0.64298015 hsa_circ_0073340 1.72721874 Up 0.00133111 0.49533889 hsa_circ_0029674 1.74809879 Up 0.00229149 0.52887377 hsa_circ_0021068 1.79691824 Up 0.00294272 0.52887377 hsa_circ_0053947 1.80953972 Up 0.02793328 0.6886992 hsa_circ_0002202 1.89666917 Up 0.00079917 0.44105722 hsa_circ_0079556 1.94764347 Up 0.00845628 0.63723776 hsa_circ_0015729 2.96958438 Up 0.02245883 0.67318317 hsa_circ_0092238 3.03306764 Up 0.02362915 0.67886653 hsa_circ_0092236 3.45575278 Up 0.03065391 0.6886992 hsa_circ_0092221 4.29199121 Up 0.03950529 0.68996252 [95]Open in a new tab Table 3. Results of Gene Ontology (GO) Enrichment Analysis of Differentially Expressed circRNAs Ontology Term Description Gene Number P-adj BP GO:0030199 Collagen fibril organization 7 0.00044787 BP GO:0043062 extracellular structure Organization 15 0.00076629 BP GO:0030198 Extracellular matrix organization 14 0.00076629 BP GO:0060840 Artery development 7 0.00694781 BP GO:0071230 Cellular response to amino acid stimulus 6 0.00694781 BP GO:0043200 Response to amino acid 7 0.01121075 BP GO:0001101 Response to acid chemical 11 0.02282114 BP GO:0045176 Apical protein localization 3 0.02282114 CC GO:0045121 Membrane raft 11 0.00284762 CC GO:0098857 Membrane microdomain 11 0.00284762 CC GO:0098589 Membrane region 11 0.00284762 CC GO:0044420 Extracellular matrix component 5 0.00284762 CC GO:0005583 Fibrillar collagen trimer 3 0.00333723 CC GO:0098643 Banded collagen fibril 3 0.00333723 CC GO:0005788 Endoplasmic reticulum lumen 10 0.00425887 CC GO:0031252 Cell leading edge 11 0.00744481 CC GO:0005901 Caveola 5 0.01094539 CC GO:0098644 Complex of collagen trimers 3 0.01126914 CC GO:0005581 Collagen trimer 5 0.01321773 CC GO:0045177 Apical part of cell 10 0.01385878 CC GO:0016324 Apical plasma membrane 9 0.01385878 CC GO:0062023 Collagen-containing extracellular matrix 10 0.01868493 CC GO:0031253 Cell projection membrane 9 0.02141473 CC GO:0044853 Plasma membrane raft 5 0.02530242 CC GO:0031256 Leading edge membrane 6 0.03027327 CC GO:0005844 Polysome 4 0.03442097 CC GO:0005911 Cell-cell junction 10 0.03442097 CC GO:0097470 Ribbon synapse 2 0.03835081 CC GO:0005925 Focal adhesion 9 0.04570731 CC GO:0005924 Cell-substrate adherens junction 9 0.04581649 CC GO:0030055 Cell-substrate junction 9 0.04674156 MF GO:0030020 Extracellular matrix structural constituent conferring tensile strength 5 0.00708066 MF GO:0005201 Extracellular matrix structural constituent 8 0.00916654 MF GO:0140104 Molecular carrier activity 5 0.00916654 MF GO:0019838 Growth factor binding 7 0.01134742 MF GO:0046332 SMAD binding 5 0.03542754 MF GO:0003779 Actin binding 11 0.04505555 [96]Open in a new tab Abbreviations: BP, biological process; CC, cellular component; MF, molecular function. Table 4. Results of KEGG Enrichment Analysis of Differentially Expressed circRNAs Term Description Gene Number P-adj hsa04974 Protein digestion and absorption 7 0.009083535 [97]Open in a new tab Identification of Differentially Expressed lncRNA in T1DM and Healthy Patients Similarly, we analyzed the lncRNA expression with the microarray [98]GSE133225. As shown in the volcano plot ([99]Figure 3A) and heatmap ([100]Figure 3B), 404 differentially expressed lncRNAs were screened (DElncRNAs, 199 up-regulated and 205 down-regulated) ([101]Table 5). Meanwhile, the top 5 chromosomal positions of these DElncRNAs are as follows: chr1 (34, 8.42%), chr2 (29, 7.18%), chr17 (25, 6.19%), chr3 (25, 6.19%), chr10 (24, 5.94%). The GO enrichment analysis results showed that the DElncRNAs were enriched in macrophage activation (GO:0042116) and microvillus (GO:0005902) ([102]Figure 3C and [103]Table 6). Figure 3. [104]Figure 3 [105]Open in a new tab The differentially expressed lncRNAs in T1DM and healthy patients. (A) Volcano plot of DElncRNAs between normal and T1DM groups. Red and green indicate up- and downregulation, respectively. (B) Heatmap of DElncRNAs between normal and T1DM groups. Red color represents increased expression, and green color represents decreased expression. The darker the color, the greater the difference of lncRNA expression. (C) Enrichment analysis of the DElncRNAs in the categories biological process and cellular component. Table 5. Differentially Expressed lncRNAs Between the Control Group and T1DM Group lncRNAs Log2FoldChange Regulation P-value P-adj lnc-MARC1-2:1 −2.571855 Down 0.002228 0.49624236 lnc-PSMG1-3:2 −2.3628597 Down 0.00610319 0.55695089 CCND2-AS1-201 −2.1767994 Down 0.00261656 0.51224337 lnc-ANGPTL2-7:1 −2.1177664 Down 0.00318539 0.53930742 [106]AL356740.2–201 −2.0532982 Down 0.0027546 0.51224337 lnc-APBA2-1:3 −2.0384649 Down 0.00358789 0.54892347 lnc-SEL1L3-10:1 −1.9247783 Down 0.00065127 0.39679443 ENPP7P13 −1.8523605 Down 0.03454029 0.72695785 lnc-MBNL2-2:1 −1.8516299 Down 0.00108059 0.42609515 lnc-CTD-2523D13.1.1–2:3 −1.8151432 Down 0.00042329 0.33998788 LOC101929733 −1.805357 Down 0.01482033 0.65476375 [107]AC011287.1–203 −1.8043227 Down 0.01357893 0.63919136 [108]AC013553.4–201 −1.7883164 Down 0.01251521 0.63775317 AL021368.3–201 −1.7524563 Down 0.02035199 0.68302181 lnc-CD5L-1:1 −1.7425319 Down 0.00420523 0.55695089 SEMA6A-AS1-206 −1.7140352 Down 0.00134151 0.4460612 LINC00299-203 −1.71106 Down 0.00391051 0.55546359 lnc-FRZB-2:2 −1.6847279 Down 0.00324333 0.53930742 GGNBP1 −1.6719447 Down 0.0166596 0.65620897 lnc-UNC5CL-7:1 −1.6687674 Down 0.00461045 0.55695089 lnc-MRPS5-13:1 −1.6546035 Down 0.00921325 0.6151086 lnc-C1orf64-1:1 −1.6395822 Down 0.01190126 0.63705043 [109]AL136979.1–201 −1.6202871 Down 0.0006092 0.39679443 lnc-CNGB1-1:3 −1.5925938 Down 0.02212688 0.6889443 AL021937.6–201 −1.5827605 Down 0.00032605 0.33391458 lnc-RASGRP1-6:1 −1.5821617 Down 2.33×10^−6 0.05960188 lnc-ANO2-4:1 −1.5733225 Down 0.00170014 0.48365219 LINC00471 −1.5517992 Down 0.01828625 0.66352772 [110]AP001363.1–201 −1.5323863 Down 0.02355621 0.69616967 [111]AC011405.1–201 −1.523797 Down 0.00820535 0.60770111 [112]AC108935.1–201 −1.5001012 Down 0.00635053 0.55695089 lnc-TBC1D3C-4:1 −1.4786853 Down 0.00403532 0.55546359 lnc-LIPI-6:1 −1.4669252 Down 0.00132802 0.4460612 lnc-FCHSD2-4:1 −1.4647594 Down 0.00223289 0.49624236 [113]AC104590.1–201 −1.458406 Down 0.00163683 0.47784335 lnc-NDFIP2-8:1 −1.4500676 Down 0.01442379 0.65361455 lnc-AL359878.1–1:1 −1.4473997 Down 0.04508299 0.74859413 lnc-NUP98-2:1 −1.4448238 Down 0.02667345 0.70331657 lnc-DTHD1-2:1 −1.4441469 Down 0.00161419 0.47784335 lnc-DCAF4L1-1:1 −1.4367953 Down 0.02450173 0.69781796 [114]AC022296.1–201 −1.4277172 Down 0.00029813 0.33391458 LINC02279-201 −1.4213164 Down 0.00907281 0.6151086 C5orf66-AS1 −1.4124554 Down 0.00199206 0.49624236 lnc-IRF5-2:1 −1.4087918 Down 0.04752968 0.75874445 lnc-FXYD2-1:2 −1.4016591 Down 0.01605233 0.65476375 ENST00000434742 −1.3965605 Down 0.04266873 0.74199989 LINC00710-210 −1.3926583 Down 0.00459619 0.55695089 lnc-RUNX1T1-6:1 −1.390228 Down 0.04310897 0.74348205 lnc-REP15-2:1 −1.3887183 Down 0.01204392 0.63775317 lnc-GLCCI1-5:1 −1.3790449 Down 0.00360051 0.54892347 lnc-TDRD5-2:2 −1.3779141 Down 0.00653613 0.56344961 lnc-TIPARP-1:1 −1.3745656 Down 1.71×10^−5 0.219024 NONHSAT144810 −1.3733309 Down 0.04223393 0.74199989 lnc-C8orf12-1:5 −1.3670614 Down 0.01262556 0.63775317 FLJ42393-201 −1.360109 Down 0.01787249 0.65667837 [115]AL031186.1–201 −1.359927 Down 0.00231239 0.50172959 NONHSAT078217 −1.3517092 Down 0.03830547 0.73920545 HSFY1P1 −1.3512769 Down 0.02395161 0.69616967 [116]AL365295.1–203 −1.3483624 Down 0.00642502 0.55846139 lnc-ST8SIA4-9:1 −1.3434237 Down 0.04271071 0.74199989 LINC01461 −1.3413799 Down 0.01143714 0.63705043 lnc-GPR27-16:1 −1.3407603 Down 0.01468499 0.65476375 [117]AC005772.1–201 −1.3381628 Down 0.00051768 0.37869313 MIR2117 −1.3345777 Down 0.00182095 0.49597572 lnc-GPR180-8:1 −1.3325294 Down 0.04785484 0.75909133 lnc-CDH19-1:1 −1.3297711 Down 0.00373595 0.55546359 lnc-MYLIP-1:1 −1.3230214 Down 0.03290443 0.7208645 lnc-[118]AC006156.1–6:1 −1.3212148 Down 0.03163903 0.72031743 LINC00326-202 −1.3131651 Down 0.002781 0.51224337 lnc-THSD7A-5:1 −1.3104044 Down 0.01270662 0.63775317 [119]AL513320.1–201 −1.3078099 Down 0.02483242 0.69822202 LOC100288570 −1.302538 Down 0.00116144 0.42609515 OR4F13P −1.3002494 Down 0.00258605 0.51224337 SKAP1-AS1-201 −1.2965689 Down 0.0399885 0.74199989 lnc-ZC3H12B-8:1 −1.2960126 Down 0.00485753 0.55695089 lnc-DDX58-6:2 −1.2919894 Down 0.04664872 0.75453224 lnc-MRPL9-1:1 −1.2821415 Down 0.0193777 0.67753348 lnc-C6orf195-20:1 −1.2797904 Down 0.00068424 0.39679443 LINC00563 −1.2751075 Down 0.04014392 0.74199989 RNU6-693P-201 −1.2734215 Down 0.00931818 0.6151086 lnc-SERP2-13:1 −1.2711219 Down 0.03525604 0.72695785 lnc-NKD2-3:8 −1.2692144 Down 0.01741431 0.65667837 lnc-CSNK1A1-6:1 −1.2661357 Down 0.03246677 0.72031743 lnc-TMEM178-4:1 −1.2653338 Down 0.01654808 0.65588218 [120]AC010280.1–201 −1.2633516 Down 0.02288955 0.69353994 [121]AC011333.1–201 −1.2601339 Down 0.01734914 0.65667837 lnc-SRY-12:1 −1.255766 Down 0.04179039 0.74199989 LOC101929541 −1.2543068 Down 0.00422143 0.55695089 lnc-IQCG-1:1 −1.2510293 Down 0.00960776 0.6151086 lnc-TRAF7-1:4 −1.250778 Down 0.02651159 0.7025969 [122]AC068051.1–202 −1.250693 Down 0.01630728 0.65588218 lnc-WSB1-9:1 −1.2499003 Down 0.00027697 0.33391458 HIPK1-AS1-202 −1.247658 Down 0.00646044 0.55880591 lnc-ANKRD65-4:1 −1.2456674 Down 0.00167491 0.48182856 lnc-RASD1-2:1 −1.2336926 Down 0.03531618 0.72695785 lnc-PTPN12-1:1 −1.2251669 Down 0.00203611 0.49624236 lnc-ASAH2B-6:1 −1.2249331 Down 0.02282058 0.69285761 lnc-VSTM2B-7:1 −1.2187025 Down 0.00664315 0.56471029 [123]AC009145.3–201 −1.2150544 Down 0.00669705 0.56471029 lnc-EXOC4-2:1 −1.2094249 Down 0.03638874 0.73000405 lnc-ASF1A-7:1 −1.2091281 Down 0.04945525 0.76055974 LOC101927915 −1.2090211 Down 0.04151546 0.74199989 MIR520D −1.2003733 Down 0.01614125 0.65476375 lnc-RP11-148O21.3.1–3:1 −1.1989594 Down 0.03101553 0.72031743 lnc-VCPIP1-2:1 −1.1940207 Down 0.01680361 0.65667837 lnc-MANEA-15:1 −1.1934022 Down 0.03073549 0.71864918 [124]AP007216.1–201 −1.1933507 Down 0.03903039 0.74199989 lnc-BOC-1:1 −1.1894086 Down 0.03214827 0.72031743 lnc-ALCAM-16:1 −1.1864006 Down 0.00010229 0.23823842 [125]AC243965.1–201 −1.1825172 Down 0.00992456 0.61994889 lnc-SNRPEP2-1:1 −1.1777925 Down 0.00505178 0.55695089 MIR8063 −1.1720035 Down 0.03554046 0.72695785 LINC01497 −1.1712102 Down 0.00396132 0.55546359 [126]AP005202.1–201 −1.1711452 Down 0.02687222 0.70508418 lnc-CA5A-14:1 −1.170243 Down 0.01880508 0.66963349 TBC1D26-AS1-201 −1.1690859 Down 0.03794326 0.73763201 lnc-RHOB-6:4 −1.164896 Down 0.00952576 0.6151086 lnc-TMEM235-1:1 −1.1644461 Down 0.02080375 0.68520443 lnc-NKAIN3-1:1 −1.1639521 Down 0.01613077 0.65476375 lnc-TFAP2A-12:1 −1.1638797 Down 0.0458381 0.75250711 NONHSAT080748 −1.1637059 Down 0.04242998 0.74199989 lnc-WDR1-2:1 −1.1612431 Down 0.01413228 0.64612284 lnc-STYK1-2:1 −1.160814 Down 0.03332132 0.72302337 lnc-C2CD4A-8:3 −1.1589171 Down 0.03249489 0.72031743 lnc-RAB9A-4:1 −1.1570636 Down 0.04423563 0.74774931 lnc-GRIK4-2:1 −1.1570003 Down 0.01043825 0.62720663 [127]AL356124.1–212 −1.1529537 Down 0.0059984 0.55695089 lnc-GRID1-10:2 −1.1509303 Down 0.00028173 0.33391458 lnc-DMRTA1-21:1 −1.1494581 Down 0.02080202 0.68520443 COPG2IT1 −1.1488501 Down 0.03280207 0.7208645 GUSBP1 −1.1442627 Down 0.03300713 0.7208645 lnc-[128]AC016251.1–18:1 −1.1426114 Down 0.01124953 0.63705043 lnc-IGHMBP2-2:1 −1.1410125 Down 0.01522257 0.65476375 lnc-CLK1-5:1 −1.1408544 Down 0.00456639 0.55695089 lnc-DDIT4L-1:1 −1.139392 Down 0.0033263 0.54489032 lnc-ATP8A2-4:1 −1.1309851 Down 0.01285546 0.63775317 [129]AC002550.1–201 −1.1258339 Down 0.03121112 0.72031743 lnc-[130]BX255923.1–4:1 −1.1254471 Down 0.02958836 0.71263333 LRRC37A6P −1.1246433 Down 0.01039373 0.62720663 lnc-THBD-3:1 −1.1181096 Down 0.01823629 0.66321547 SMIM2-IT1 −1.1152686 Down 0.04821159 0.75909133 lnc-EIF2AK3-10:1 −1.1129693 Down 0.00094609 0.41823037 [131]AC072039.2–201 −1.1023779 Down 0.04427089 0.74774931 [132]AC073655.1–201 −1.1010143 Down 0.00438297 0.55695089 lnc-HECA-8:3 −1.1007561 Down 0.01730192 0.65667837 lnc-CAMK2N2-1:1 −1.100534 Down 0.02254575 0.69130412 lnc-RET-2:1 −1.0994363 Down 0.02204275 0.6889443 [133]AC006482.1–201 −1.0943276 Down 0.01606638 0.65476375 NONHSAT066757 −1.0893525 Down 0.02619728 0.7025969 lnc-PCIF1-1:1 −1.0831588 Down 0.03331068 0.72302337 lnc-RGS9-1:9 −1.0808278 Down 0.04328182 0.74348205 lnc-TMEM63B-3:1 −1.0806828 Down 0.03297302 0.7208645 [134]AL354726.1–201 −1.0779947 Down 0.03804582 0.7382395 lnc-VPS45-5:1 −1.0767237 Down 0.03551093 0.72695785 MIR100HG-204 −1.0749286 Down 0.00478367 0.55695089 lnc-ERMN-3:1 −1.0724303 Down 0.01323341 0.63919136 lnc-POM121L12-9:1 −1.0701442 Down 0.01424926 0.64799971 LINC02399-201 −1.0677909 Down 0.00159699 0.47784335 ZNF385D-AS2 −1.0675014 Down 0.03541215 0.72695785 lnc-CCNJL-3:1 −1.0661945 Down 0.03740759 0.73503181 lnc-SLC4A3-7:4 −1.0657752 Down 0.00420941 0.55695089 [135]AC096666.1–201 −1.0645687 Down 0.0475234 0.75874445 TRAPPC12-AS1-201 −1.0621034 Down 0.00527019 0.55695089 [136]AC010973.1–201 −1.0620397 Down 0.01113385 0.63705043 lnc-PYGO1-3:1 −1.0617362 Down 0.00735041 0.57770209 NONHSAT106126 −1.0615194 Down 0.00454088 0.55695089 lnc-ZNF33A-7:1 −1.0611652 Down 0.02394318 0.69616967 [137]AC021097.1–201 −1.0607721 Down 0.00678068 0.56733936 lnc-SNX11-9:1 −1.0565877 Down 0.04932529 0.75985275 LINC00092-202 −1.0542115 Down 0.00493655 0.55695089 LOC100130417 −1.0441384 Down 0.02061929 0.68461156 lnc-DACT1-2:1 −1.0422563 Down 0.00276522 0.51224337 lnc-CACNA1E-5:3 −1.0418233 Down 0.032085 0.72031743 lnc-KCNJ2-2:1 −1.0409158 Down 0.03770802 0.73763201 ZNF451-AS1-202 −1.0407145 Down 0.0199397 0.68003654 [138]AC022509.1–203 −1.0393619 Down 0.04632896 0.75407344 [139]AL162253.1–201 −1.039287 Down 0.04553105 0.75046636 LINC01339 −1.0376761 Down 0.01322858 0.63919136 RNU4-30P-201 −1.03405 Down 0.04484526 0.74859413 lnc-ZNF527-3:1 −1.0331657 Down 0.00495913 0.55695089 lnc-VSTM4-1:3 −1.0311378 Down 0.03884105 0.74199989 lnc-ORMDL2-3:1 −1.0308522 Down 0.03578571 0.7283161 lnc-AKIP1-5:1 −1.0271559 Down 0.02023333 0.68302181 [140]AL359091.4–201 −1.0270896 Down 0.04632883 0.75407344 lnc-PPIAL4G-24:1 −1.0236308 Down 0.02813286 0.70952942 LOC100506679 −1.0230377 Down 0.00087856 0.41823037 lnc-TSSC1-12:1 −1.0215854 Down 0.00560415 0.55695089 LOC100505984 −1.0208834 Down 0.0255792 0.7025969 lnc-FAM50B-12:1 −1.0196309 Down 0.02412553 0.69616967 lnc-ALG9-1:1 −1.0176951 Down 0.00552229 0.55695089 [141]AC096669.1–201 −1.0157852 Down 0.03891937 0.74199989 lnc-ZNF135-1:1 −1.0126176 Down 0.02399892 0.69616967 lnc-C2orf65-7:1 −1.0125274 Down 0.03958279 0.74199989 NONHSAT093043 −1.0122218 Down 0.0244619 0.69781796 lnc-MARCKS-2:1 −1.0108829 Down 0.01484675 0.65476375 lnc-ERI1-5:1 −1.0096415 Down 0.00105398 0.42609515 lnc-[142]AC011484.1–1:1 −1.0085847 Down 0.02523925 0.69822202 lnc-C15orf41-16:1 −1.0085698 Down 0.00270442 0.51224337 AC006116.7–201 −1.0082255 Down 0.0092013 0.6151086 [143]AL354760.1–201 −1.007775 Down 0.02302132 0.69368951 lnc-HS3ST3A1-6:1 −1.005627 Down 0.01277075 0.63775317 LINC01007 −1.0051638 Down 0.04174436 0.74199989 lnc-FSTL5-2:1 −1.0044016 Down 0.02732332 0.70738927 lnc-OR10G2-7:1 −1.0040498 Down 0.02589504 0.7025969 lnc-SCN11A-1:3 −1.0003752 Down 0.01675468 0.65667837 KRT8P41 1.00323605 Up 0.0157024 0.65476375 lnc-TOMM70A-2:1 1.00437111 Up 0.02094011 0.68579407 ST20-AS1-201 1.00542536 Up 0.00950719 0.6151086 lnc-MCM3AP-2:1 1.00595783 Up 0.04176408 0.74199989 NONHSAT103382 1.00610895 Up 0.01949203 0.67753348 lnc-ZNF729-1:1 1.00878014 Up 0.00141575 0.46126795 lnc-ZNF613-1:5 1.00881485 Up 0.00992771 0.61994889 ZKSCAN7-AS1-201 1.01240919 Up 0.01157844 0.63705043 LINC00173 1.01400481 Up 0.04488089 0.74859413 lnc-SCARF1-1:1 1.0156664 Up 0.00981816 0.61762722 NONHSAT018354 1.01593666 Up 0.03530828 0.72695785 lnc-FMN2-5:1 1.01602171 Up 0.0002276 0.32373463 lnc-SGIP1-3:1 1.01645757 Up 0.01641438 0.65588218 LINC01640-201 1.01688724 Up 0.04089227 0.74199989 [144]AC091906.1–201 1.01953621 Up 0.03271348 0.7208645 lnc-FAM98A-4:1 1.02021781 Up 7.97×10^−5 0.23823842 LINC02531-201 1.0290261 Up 0.0217835 0.6875777 lnc-MKKS-2:1 1.02955928 Up 0.0127837 0.63775317 lnc-VPS45-1:1 1.03014965 Up 0.02882574 0.71150768 lnc-ATP6AP2-5:1 1.03058486 Up 0.01059718 0.62720663 lnc-SSX1-3:1 1.03120136 Up 0.00345991 0.54892347 lnc-TMEM144-6:1 1.03146297 Up 0.00218147 0.49624236 [145]AC064805.1–203 1.03207632 Up 0.01476632 0.65476375 [146]AL049781.1–201 1.03367342 Up 0.03188715 0.72031743 lnc-CD38-5:1 1.03537123 Up 0.02413739 0.69616967 lnc-RDH10-3:1 1.0354704 Up 0.00905218 0.6151086 MIR527 1.03634444 Up 0.04629443 0.75407344 lnc-IL36B-3:1 1.04032276 Up 0.03473821 0.72695785 lnc-AP3S1-8:1 1.04706344 Up 0.01681226 0.65667837 lnc-AC004381.6.1–2:2 1.04706933 Up 0.03502406 0.72695785 lnc-ARL11-1:1 1.05123661 Up 0.04263733 0.74199989 lnc-DEFB116-8:1 1.05366198 Up 0.02045757 0.68302181 lnc-COBLL1-2:1 1.05373818 Up 0.00428499 0.55695089 lnc-TLX1-6:4 1.05385144 Up 0.02973516 0.71383843 lnc-FAM135A-3:1 1.0543549 Up 0.00588203 0.55695089 lnc-TFF3-2:1 1.0556941 Up 0.00929413 0.6151086 lnc-NBPF6-1:5 1.06191301 Up 0.0039231 0.55546359 LINC00470-208 1.06395774 Up 0.02171233 0.6875777 lnc-FREM3-4:1 1.06877234 Up 0.03813847 0.7386227 lnc-ZAP70-2:44 1.0688365 Up 0.01504184 0.65476375 lnc-ZSCAN5A-1:1 1.06985443 Up 0.01950186 0.67753348 lnc-DDHD1-7:1 1.07032663 Up 0.00334132 0.54489032 TMEM18-DT-201 1.07452939 Up 0.00488947 0.55695089 ENST00000614227 1.07841048 Up 0.00384573 0.55546359 lnc-NADKD1-2:1 1.07972767 Up 0.02298006 0.69368951 lnc-WDR96-3:1 1.08166487 Up 0.02824276 0.70952942 [147]AC106028.4–201 1.08382489 Up 0.04826811 0.75909133 lnc-LYSMD3-2:1 1.0840707 Up 0.01190799 0.63705043 RNU6-709P-201 1.08652258 Up 0.0044661 0.55695089 lnc-FAM75B-2:1 1.08830209 Up 0.02084896 0.68520443 lnc-CDYL-9:1 1.08948305 Up 0.00637373 0.55695089 lnc-PDE1C-2:3 1.09008387 Up 0.00078375 0.41823037 lnc-SRRM1-4:1 1.09019086 Up 0.01620667 0.65476375 [148]AC012363.1–201 1.09404463 Up 0.04399763 0.74634378 lnc-RP1L1-3:3 1.09943997 Up 0.01034911 0.62720663 lnc-TBPL2-3:1 1.09976307 Up 0.02214589 0.6889443 [149]AC091078.1–201 1.10348942 Up 0.01206545 0.63775317 [150]AC079456.1–201 1.10454579 Up 0.00559852 0.55695089 lnc-ASPH-5:3 1.10750927 Up 0.02233274 0.69018461 lnc-EXTL3-1:3 1.11176621 Up 0.02864791 0.71004105 TMEM108-AS1-201 1.11243266 Up 0.04766525 0.75874445 LINC00463 1.1130875 Up 0.02148542 0.6875777 TYMSOS-202 1.11588444 Up 0.00210834 0.49624236 lnc-FAM19A3-7:1 1.11995024 Up 4.32×10^−5 0.23823842 [151]AC011481.1–201 1.1228884 Up 0.02649529 0.7025969 ATRNL1 1.12368531 Up 0.01534705 0.65476375 SNHG14-221 1.12569191 Up 0.04719373 0.75708084 lnc-ACAD11-2:1 1.12954103 Up 0.01867463 0.66684299 [152]AC127496.3–201 1.13361155 Up 0.00180459 0.49597572 lnc-FAM27B-9:1 1.13529595 Up 0.01792398 0.65667837 lnc-ANO6-2:1 1.14150763 Up 0.00932979 0.6151086 lnc-BAG4-4:1 1.14644342 Up 0.02936139 0.71263333 lnc-ABCA1-1:2 1.14734442 Up 0.00747609 0.58535254 lnc-GGPS1-7:1 1.14849917 Up 0.01982258 0.68003654 lnc-ITPRIP-7:1 1.14881355 Up 0.02032843 0.68302181 lnc-PCBP1-4:1 1.15063821 Up 0.00625079 0.55695089 lnc-PABPC3-3:2 1.15120963 Up 0.00091832 0.41823037 lnc-HERC4-1:1 1.15522135 Up 0.03708868 0.73471054 lnc-IQCH-7:1 1.1603186 Up 0.01001295 0.62174278 lnc-C16orf78-5:3 1.16644237 Up 8.81×10^−5 0.23823842 C1QTNF7-AS1-202 1.17053152 Up 0.00916598 0.6151086 lnc-VASH2-1:1 1.17220568 Up 0.04245329 0.74199989 LINC01255-204 1.17230984 Up 0.00953825 0.6151086 lnc-ATG3-2:1 1.17235799 Up 0.01125376 0.63705043 lnc-GLT1D1-5:1 1.17473163 Up 0.04455268 0.74859413 lnc-[153]CR392000.1–2:1 1.17483834 Up 0.04007513 0.74199989 lnc-HMGB2-5:1 1.17590206 Up 0.02536006 0.69966978 lnc-CDY2A-13:1 1.18188326 Up 0.01485835 0.65476375 [154]AC023355.1–202 1.1849183 Up 0.01732148 0.65667837 lnc-USP12-5:2 1.18622738 Up 0.04358103 0.74483576 LOC101929080 1.19054239 Up 0.01223231 0.63775317 lnc-KCNC2-5:1 1.19486915 Up 0.009252 0.6151086 lnc-KNTC1-4:1 1.19535911 Up 0.00297243 0.53593679 lnc-JAM3-8:1 1.19852384 Up 0.00257337 0.51224337 lnc-NKX6-1-10:1 1.20120674 Up 0.01409262 0.64546217 lnc-ARG2-1:2 1.20386745 Up 0.00126408 0.43152476 lnc-KALRN-4:1 1.20497602 Up 0.00582578 0.55695089 lnc-CORO2B-1:2 1.20602566 Up 0.00664972 0.56471029 lnc-URB2-1:3 1.20715033 Up 0.02185892 0.68799902 lnc-HS3ST3A1-5:2 1.21290644 Up 0.04894508 0.75985275 Z98885.3–201 1.21299164 Up 0.01621373 0.65476375 lnc-WDR64-2:2 1.21682833 Up 0.04578576 0.75240869 LOC101929452 1.2233498 Up 0.03206412 0.72031743 lnc-PAICS-4:1 1.22411726 Up 0.0006972 0.39679443 [155]AL020994.1–201 1.2262244 Up 0.00037776 0.33998788 lnc-CNIH3-1:1 1.2316038 Up 0.00010236 0.23823842 PRNCR1 1.2406871 Up 0.00123666 0.43152476 [156]AC024475.1–201 1.24543291 Up 0.02421639 0.69616967 lnc-DDX52-2:1 1.24950582 Up 0.00022629 0.32373463 lnc-SLFN12-6:1 1.24993787 Up 0.03623298 0.73000405 [157]AC093297.1–201 1.26032356 Up 0.03683869 0.73355985 U1.18–201 1.26323937 Up 0.00602542 0.55695089 lnc-GTPBP5-3:1 1.26463283 Up 0.03100912 0.72031743 LINC02773-201 1.27552196 Up 0.00387626 0.55546359 lnc-FAM104A-4:2 1.2756097 Up 0.00884705 0.6151086 lnc-SYCP2-3:1 1.27585656 Up 0.01741856 0.65667837 NONHSAT106296 1.28232348 Up 0.02753193 0.70738927 lnc-TMEM123-3:2 1.28431214 Up 0.00636859 0.55695089 LOC102723833 1.28894382 Up 0.00193168 0.49624236 lnc-GPR149-4:1 1.29256774 Up 0.00893933 0.6151086 lnc-SLCO4C1-4:1 1.29343344 Up 0.02627738 0.7025969 [158]AL359541.1–201 1.2959487 Up 0.009658 0.6151086 ATP2B1-AS1-201 1.29766918 Up 0.00356845 0.54892347 [159]AP000879.1–202 1.29942575 Up 0.00578872 0.55695089 lnc-RP11-6L6.2.1–3:1 1.3032656 Up 0.01303033 0.63911018 LOC102546298 1.30753746 Up 0.00014704 0.27188326 lnc-ZCCHC9-2:5 1.30773357 Up 0.01041044 0.62720663 lnc-ITGB1-4:2 1.31033236 Up 0.00767846 0.59393265 lnc-RP11-257K9.7.1–3:1 1.31103839 Up 0.01633508 0.65588218 LINC02864-202 1.31194048 Up 0.01303027 0.63911018 LINC01855-201 1.32678547 Up 0.00081184 0.41823037 lnc-C8orf4-1:2 1.33018827 Up 0.00593828 0.55695089 lnc-RP11-150O12.3.1–1:4 1.34017651 Up 0.01509456 0.65476375 lnc-ZNF503-AS2-9:1 1.34488751 Up 0.03296829 0.7208645 [160]AC120498.2–201 1.34578622 Up 0.00320335 0.53930742 lnc-HEATR4-5:1 1.3461323 Up 0.03623736 0.73000405 lnc-CNR1-1:2 1.35206876 Up 0.00627778 0.55695089 lnc-SMYD5-1:4 1.35280066 Up 0.00601195 0.55695089 lnc-NUPL1-1:1 1.35697674 Up 0.02392115 0.69616967 lnc-AKR1E2-5:1 1.35847468 Up 0.01769903 0.65667837 [161]AC012314.2–201 1.35985353 Up 0.03496286 0.72695785 lnc-CNDP2-1:1 1.36188928 Up 0.00584868 0.55695089 lnc-CHGA-2:1 1.3642467 Up 0.02269448 0.69285761 MIR1307 1.36484241 Up 0.03613377 0.73000405 lnc-SRGN-3:1 1.37117291 Up 0.00300049 0.53721319 lnc-XRCC2-3:1 1.38735139 Up 0.00200603 0.49624236 LRRK2-DT-202 1.39577039 Up 0.01113659 0.63705043 [162]AC113133.1–203 1.43171942 Up 0.00455193 0.55695089 lnc-CCL3-1:2 1.43199469 Up 0.02692513 0.70508418 lnc-RTKN2-5:1 1.43324395 Up 0.00204034 0.49624236 [163]BX005019.1–201 1.43992263 Up 0.0338234 0.72437788 lnc-C14orf182-4:1 1.45445268 Up 0.01695345 0.65667837 [164]AC034199.1–201 1.47353584 Up 0.0213565 0.6875777 lnc-LYZL1-10:1 1.48259417 Up 0.00124885 0.43152476 lnc-LRIG1-3:1 1.48289858 Up 0.00178858 0.49597572 [165]AL391241.1–201 1.48399065 Up 0.03316116 0.72302337 lnc-MAP1LC3B2-4:3 1.49320191 Up 0.00670515 0.56471029 lnc-RAD51B-1:1 1.49785989 Up 0.00014303 0.27188326 MIR425 1.50669826 Up 0.0042996 0.55695089 lnc-SIM2-2:1 1.52947082 Up 0.04100787 0.74199989 PRMT5-AS1-206 1.53103618 Up 0.00853801 0.6151086 [166]AC027018.1–202 1.53360865 Up 0.01496409 0.65476375 lnc-ARF6-5:1 1.5402516 Up 0.00426956 0.55695089 lnc-KCNK9-3:1 1.55537316 Up 8.35×10^−5 0.23823842 LOC102724484 1.55813648 Up 0.00484276 0.55695089 lnc-VAMP3-3:1 1.55906933 Up 0.01857284 0.66521456 lnc-MRPS18A-2:6 1.5595027 Up 0.00187188 0.49624236 lnc-TACR2-5:1 1.56018317 Up 0.03954105 0.74199989 lnc-APCDD1L-1:1 1.56781969 Up 0.00071636 0.3987193 lnc-RILP-1:5 1.57733865 Up 0.01232391 0.63775317 NONHSAT106835 1.58291652 Up 0.04113014 0.74199989 [167]AC066595.1–201 1.59152878 Up 0.00607687 0.55695089 [168]AP002505.2–201 1.65111587 Up 0.00528326 0.55695089 lnc-ROPN1B-8:1 1.66748053 Up 0.0033198 0.54489032 lnc-NLK-1:2 1.66793517 Up 0.01702869 0.65667837 lnc-SH3BGRL2-8:1 1.68256761 Up 0.01627335 0.65588218 LINC00862 1.69076057 Up 0.04360851 0.74483576 lnc-XK-2:1 1.69608599 Up 0.02384559 0.69616967 [169]AL606468.1–201 1.72966979 Up 0.00784283 0.59809568 lnc-DRD3-2:1 1.73507434 Up 0.0002036 0.32373463 lnc-ASMT-7:1 1.77985488 Up 0.00534204 0.55695089 [170]AC022001.3–201 1.78553082 Up 0.01479698 0.65476375 [171]AC090643.2–201 1.83684053 Up 0.00079596 0.41823037 NONHSAT106837 1.84066898 Up 0.02058467 0.68445357 [172]AC103993.1–202 1.85414231 Up 0.00017245 0.29435292 lnc-CPXM2-2:2 1.86775188 Up 0.01688355 0.65667837 SNHG21 1.90852825 Up 0.00532982 0.55695089 [173]AC116021.1–201 1.93990875 Up 0.02097564 0.68579407 LOC102467217 1.9623212 Up 0.00440907 0.55695089 lnc-C2orf62-1:1 1.96238874 Up 0.01728119 0.65667837 PELATON-201 2.00463147 Up 0.03488425 0.72695785 lnc-C5-1:1 2.0585191 Up 0.01120735 0.63705043 lnc-PON2-3:1 2.06777784 Up 0.02628724 0.7025969 lnc-IFNA2-2:1 2.17522445 Up 0.0119433 0.63705043 [174]AL359258.1–201 2.17725336 Up 0.01246482 0.63775317 lnc-CEACAM6-1:1 2.22056145 Up 0.02321939 0.69449317 lnc-EVI2A-1:1 2.25337956 Up 0.00361694 0.54892347 lnc-CXCL3-1:1 2.28502109 Up 0.03936439 0.74199989 lnc-SRGN-4:1 2.3926122 Up 0.00530242 0.55695089 [175]Open in a new tab Table 6. Results of Gene Ontology (GO) Enrichment Analysis of Differentially Expressed lncRNAs Ontology Term Description Gene Number P-adj BP GO:0042116 Macrophage activation 5 0.01572240 BP GO:0043030 Regulation of macrophage activation 4 0.01885761 CC GO:0005902 Microvillus 4 0.02267082 [176]Open in a new tab Abbreviations: BP, biological process; CC, cellular component. Identification of Differentially Expressed mRNA in T1DM and Healthy Patients Subsequently, the differentially expressed mRNAs between the normal and T1DM groups were analyzed. As the volcano plot ([177]Figure 4A) and heatmap ([178]Figure 4B) indicated, there were 73 differentially expressed mRNAs (DEmRNAs, 31 up-regulated and 42 down-regulated) ([179]Table 7). Most of them were located at chr2 (7, 9.59%), chr7 (6, 8.22%), chr17 (5, 6.85%), chr20 (5, 6.85%), chr12 (4, 5.48%). In addition, GO enrichment analysis showed that the DEmRNAs were enriched in prostaglandin receptor activity (GO:0004955), prostanoid receptor activity (GO:0004954), and BMP binding (GO:0036122) ([180]Figure 4C and [181]Table 8). Figure 4. [182]Figure 4 [183]Open in a new tab The differentially expressed mRNAs in T1DM and healthy patients. (A) Volcano plot of DEmRNAs between normal and T1DM groups. Red and green indicate up- and downregulation, respectively. (B) Heatmap of DEmRNAs between normal and T1DM groups. Red color represents increased expression, and green color represents decreased expression. The darker the color, the greater the difference in mRNA expression. (C) Enrichment analysis of the DEmRNAs in the category molecular function. Table 7. Differentially Expressed mRNAs Between the Control Group and T1DM Group mRNAs Log2FoldChange Regulation P-value P-adj RBFOX1 −2.3079121 Down 0.00020929 0.48868466 FAM132B −1.9940805 Down 0.00498156 0.78986357 SLFNL1 −1.9223862 Down 0.00176092 0.71338425 CLDN22 −1.7965769 Down 0.00866828 0.8200064 GNAL −1.7755788 Down 0.01707197 0.82671544 MUC15 −1.5965074 Down 0.00413517 0.78986357 CA8 −1.5357652 Down 0.01131812 0.82671544 PTGDR −1.5165361 Down 0.02574051 0.82671544 TEX13A −1.495935 Down 0.01513717 0.82671544 TAAR2 −1.4635903 Down 0.00606045 0.78986357 KIR3DL1 −1.4479969 Down 0.02527008 0.82671544 COL6A3 −1.4263206 Down 0.0018801 0.71338425 B4GALNT2 −1.3947065 Down 0.01298325 0.82671544 PARD3 −1.3582746 Down 0.01926125 0.82671544 SORBS1 −1.341606 Down 0.01356421 0.82671544 GPR32 −1.3306212 Down 0.0041603 0.78986357 DUOX2 −1.3208459 Down 0.01957626 0.82671544 HPGD −1.3088539 Down 0.01853011 0.82671544 NNMT −1.2274537 Down 0.04763409 0.82671544 TMEM74 −1.2255201 Down 0.04530755 0.82671544 COL6A2 −1.2224407 Down 0.02822533 0.82671544 HSPB8 −1.2153355 Down 0.01531611 0.82671544 BFSP1 −1.1831939 Down 0.03922896 0.82671544 GNG11 −1.179029 Down 0.00163335 0.71338425 GPR1 −1.1631327 Down 0.02166454 0.82671544 B3GALT5 −1.1584697 Down 0.01946241 0.82671544 C20orf173 −1.1568903 Down 0.01892708 0.82671544 CYP11B1 −1.152487 Down 0.00018277 0.48868466 DHH −1.1517769 Down 0.00194518 0.71338425 CRYM −1.1448803 Down 0.00232428 0.71338425 SMKR1 −1.138156 Down 0.04519693 0.82671544 BPIFB3 −1.1194083 Down 0.03620019 0.82671544 FAM150B −1.1105272 Down 0.04200652 0.82671544 TEX11 −1.0988657 Down 0.00098015 0.71338425 NPR3 −1.0702284 Down 0.03640359 0.82671544 ATP13A4 −1.0357916 Down 0.04369288 0.82671544 CAMK2N2 −1.0343627 Down 0.00515457 0.78986357 KIR2DL3 −1.0313509 Down 0.03893691 0.82671544 CACNA2D2 −1.0155401 Down 0.02373916 0.82671544 WDR76 −1.0120059 Down 0.00116238 0.71338425 GPR180 −1.0109237 Down 0.00332039 0.78986357 AMHR2 −1.0089921 Down 0.03106529 0.82671544 PCDHB15 1.00754421 Up 0.01257116 0.82671544 MARCKS 1.02701386 Up 0.03176063 0.82671544 DEFB123 1.02969089 Up 0.04036705 0.82671544 DNAJB7 1.05742045 Up 0.04277946 0.82671544 C2CD4B 1.0577298 Up 0.02772476 0.82671544 IL6 1.05994453 Up 0.04788638 0.82671544 OR2L13 1.07004067 Up 0.04427013 0.82671544 C17orf64 1.07345437 Up 0.01738992 0.82671544 SGK1 1.10667874 Up 0.03799544 0.82671544 COMP 1.11621286 Up 0.01328963 0.82671544 RASSF8 1.1211237 Up 0.0268822 0.82671544 SLC6A14 1.12250998 Up 0.00605879 0.78986357 RAPGEF5 1.13847388 Up 0.02042072 0.82671544 GREM2 1.18378203 Up 0.00260009 0.71338425 ARRDC3 1.18980995 Up 0.00721663 0.78986357 FILIP1L 1.20891948 Up 0.00719201 0.78986357 ADGRG4 1.20976755 Up 0.01358302 0.82671544 ASIC2 1.21384452 Up 0.01333649 0.82671544 MARCH1 1.26722335 Up 0.02731178 0.82671544 AGXT 1.28961174 Up 0.00580496 0.78986357 HSPA12A 1.29400344 Up 0.04457166 0.82671544 C9orf152 1.34773511 Up 0.00068838 0.71338425 MAPT 1.38818206 Up 0.00264472 0.71338425 DOCK4 1.43931041 Up 0.01074391 0.82671544 SKOR1 1.46453595 Up 0.01818479 0.82671544 CXCL13 1.52896795 Up 0.01173074 0.82671544 SLC5A7 1.57904371 Up 0.04645311 0.82671544 LOC388780 1.58723305 Up 0.01831872 0.82671544 CCL8 1.64314463 Up 0.02259273 0.82671544 PDK4 1.68428709 Up 0.02094083 0.82671544 MYO7B 1.80214766 Up 0.01684902 0.82671544 [184]Open in a new tab Table 8. Results of Gene Ontology (GO) Enrichment Analysis of Differentially Expressed mRNAs Ontology Term Description Gene Number P-adj MF GO:0004955 Prostaglandin receptor activity 2 0.043054 MF GO:0004954 Prostanoid receptor activity 2 0.043054 MF GO:0036122 BMP binding 2 0.04305384 [185]Open in a new tab Abbreviation: MF, molecular function. The circRNA-lncRNA-miRNA-mRNA Network in T1DM Due to the large number of differentially expressed circRNAs and lncRNAs, we further analyzed their correlation with the DEmRNAs expression and constructed the circRNA-lncRNA-mRNA network using r>0.7 as the screening criteria ([186]Figure 5). Meanwhile, according to the ceRNA hypothesis, lncRNA and circRNA can function as miRNA sponges that bind to miRNA and inhibit the regulation of miRNAs on its target mRNAs, thereby indirectly regulating gene expression. Thus, we predicted the miRNAs targeting the DEcircRNAs and DElncRNAs and analyzed their expression using the dataset [187]GSE133217 ([188]Table 9). After screening, the circRNA-lncRNA-miRNA-mRNA network was visualized using Cytoscape software ([189]Figure 6). For example, hsa_circ_0002202 was identified as ceRNA of miR-495-3p, miR-668-3p, miR-508-3p, miR-487a-3p, which targeted GREM2. lncRNA LINC01007 regulated HSPB8 by competing for miR-33b-5p, miR-1321, and miR-455-3p. Figure 5. [190]Figure 5 [191]Open in a new tab The circRNA-lncRNA-mRNA network. The round nodes represent DEcircRNAs, the rhombic nodes represent DElncRNAs, the v-type nodes represent DEmRNAs. The up or down-regulated genes are represented in red and green, respectively. Table 9. The Fold Change of All miRNAs Between the Control Group and T1DM Group miRNAs Log2FoldChange Regulation P-value P-adj miR-1-3p −1.5165809 Down 0.00670577 0.40231598 miR-133b −1.2850481 Down 0.00702946 0.40231598 miR-99b-5p −0.8676123 Down 0.03302164 0.59871978 let-7e-5p −0.7792672 Down 0.03530638 0.59871978 miR-125a-5p −0.7761986 Down 0.05533304 0.64056718 miR-6885-5p −0.637504 Down 1.38×10^−6 0.00354783 miR-551b-3p −0.5977145 Down 0.01706182 0.53220869 miR-10a-5p −0.5042807 Down 0.04874767 0.61412501 miR-181a-2-3p −0.4754952 Down 0.00897879 0.40696367 miR-27b-3p −0.4519303 Down 0.07953434 0.68910078 miR-151a-3p −0.4402091 Down 0.02080807 0.53734625 miR-139-5p −0.4381705 Down 0.04665277 0.61412501 miR-151b −0.4337404 Down 0.00166047 0.32405862 miR-584-5p −0.4115123 Down 0.24226951 0.80715125 miR-151a-5p −0.4054726 Down 0.00857359 0.40696367 miR-5787 −0.4016736 Down 0.00690767 0.40231598 miR-130a-3p −0.3983994 Down 0.06518421 0.65598378 miR-133a-3p −0.3784617 Down 0.01526582 0.49284222 miR-431-5p −0.376715 Down 0.26619136 0.82438552 miR-30a-5p −0.3686175 Down 0.04189063 0.60118096 miR-23b-3p −0.3650878 Down 0.06512818 0.65598378 miR-598-3p −0.3548441 Down 0.00450404 0.34045223 miR-98-5p −0.3512228 Down 0.02419159 0.55019809 miR-126-5p −0.3460713 Down 0.10065779 0.73085631 miR-3120-3p −0.3425895 Down 0.00372022 0.34045223 miR-330-3p −0.3418255 Down 0.04863712 0.61412501 miR-6085 −0.3367 Down 0.01118897 0.43937422 miR-196b-5p −0.3352881 Down 0.05202185 0.63253996 miR-324-5p −0.3283337 Down 0.05990781 0.64832335 miR-210-3p −0.3265283 Down 0.30730975 0.84469096 miR-326 −0.3226899 Down 0.04104522 0.60118096 miR-181d-5p −0.3203042 Down 0.04674485 0.61412501 miR-335-5p −0.2992288 Down 0.28050619 0.83108541 miR-5739 −0.2981961 Down 0.00422458 0.34045223 miR-126-3p −0.293697 Down 0.05433041 0.64056718 miR-590-5p −0.2899434 Down 0.04821654 0.61412501 miR-146a-5p −0.2839604 Down 0.1538926 0.75393664 miR-148a-3p −0.28039 Down 0.23451265 0.80105138 miR-6756-5p −0.2760184 Down 0.00400347 0.34045223 miR-199a-3p −0.2669967 Down 0.18245092 0.77350881 miR-28-5p −0.2650704 Down 0.00020694 0.11527458 miR-128-3p −0.2599197 Down 0.04105635 0.60118096 miR-301a-3p −0.2587877 Down 0.1947074 0.77997491 miR-652-3p −0.2571135 Down 0.014974 0.49284222 miR-1301-3p −0.2557511 Down 0.01179643 0.43937422 miR-379-5p −0.2531956 Down 0.355301 0.8588192 miR-181c-5p −0.2521543 Down 0.13770206 0.75376261 miR-432-5p −0.2503287 Down 0.48408203 0.90449982 miR-18b-5p −0.2457859 Down 0.00032042 0.11763941 miR-194-5p −0.2451756 Down 0.22699131 0.79102241 miR-127-3p −0.2446309 Down 0.33136688 0.85489649 miR-223-3p −0.2440992 Down 0.01055265 0.43937422 miR-32-5p −0.2428206 Down 0.0475609 0.61412501 miR-328-3p −0.2426408 Down 0.04244989 0.60118096 miR-132-3p −0.2426316 Down 0.07861796 0.68910078 let-7f-5p −0.2425701 Down 0.01112698 0.43937422 miR-493-5p −0.2404954 Down 0.29956191 0.83872374 miR-27a-3p −0.2375163 Down 0.07375852 0.68406327 miR-1307-5p −0.2345506 Down 0.04837714 0.61412501 miR-495-3p −0.2335808 Down 0.44444021 0.88952595 miR-6165 −0.2328824 Down 0.04757592 0.61412501 miR-221-3p −0.2320004 Down 0.19653159 0.77997491 miR-4317 −0.2301339 Down 9.82×10^−5 0.08408842 miR-374c-5p −0.2292803 Down 0.02737626 0.58146271 miR-152-3p −0.2286181 Down 0.06717209 0.65890175 miR-497-5p −0.2266935 Down 0.08775824 0.71090581 miR-195-5p −0.2257144 Down 0.11867951 0.74226488 miR-744-5p −0.2244425 Down 0.11526467 0.74226488 miR-543 −0.2168851 Down 0.13054129 0.74892227 miR-7-1-3p −0.2147568 Down 0.00184957 0.32405862 miR-17-3p −0.2126031 Down 0.07709504 0.68910078 miR-22-5p −0.2119735 Down 0.00065497 0.15302397 miR-6073 −0.2022809 Down 0.47456765 0.8954764 miR-26a-5p −0.2017921 Down 0.03685477 0.59871978 miR-148b-3p −0.2014556 Down 0.27332485 0.83107769 miR-22-3p −0.2014406 Down 0.00809954 0.40696367 miR-136-5p −0.1997377 Down 0.06492627 0.65598378 miR-376c-3p −0.1996448 Down 0.64319632 0.95274614 miR-199a-5p −0.1994898 Down 0.35912007 0.8588192 miR-340-5p −0.198198 Down 0.28288034 0.83193599 miR-769-5p −0.1956911 Down 0.22581488 0.79102241 miR-1271-5p −0.1944416 Down 0.19561173 0.77997491 miR-224-5p −0.1934675 Down 0.68365226 0.95853044 miR-6852-5p −0.191647 Down 0.00589685 0.38858751 miR-337-5p −0.1901206 Down 0.36210628 0.8588192 miR-625-5p −0.1893543 Down 0.54798536 0.92261663 miR-376a-3p −0.1877679 Down 0.65014785 0.95321673 miR-101-3p −0.1823045 Down 0.36292288 0.8588192 miR-487a-3p −0.1822157 Down 0.16729778 0.76915081 miR-411-5p −0.1820523 Down 0.11624338 0.74226488 miR-33a-5p −0.1803366 Down 0.1091139 0.74226488 miR-2355-5p −0.1784709 Down 0.01806897 0.53734625 miR-182-5p −0.1775695 Down 0.00022427 0.11527458 miR-421 −0.1771404 Down 0.03728568 0.59871978 miR-339-5p −0.1761355 Down 0.1359837 0.75376261 miR-186-5p −0.1734146 Down 0.14060276 0.75376261 miR-10b-5p −0.1714752 Down 0.00027399 0.11735825 miR-5584-3p −0.1686341 Down 0.01165649 0.43937422 miR-215-5p −0.1682987 Down 0.30023651 0.83872374 miR-320c −0.1660735 Down 0.14388218 0.75376261 miR-154-3p −0.1638598 Down 0.20356636 0.77997491 miR-30b-5p −0.1626831 Down 0.00529837 0.36854655 miR-18a-5p −0.1601252 Down 0.30503491 0.83933588 miR-505-5p −0.159129 Down 0.03015598 0.59616058 miR-146b-5p −0.1575493 Down 0.29357044 0.83872374 miR-339-3p −0.1564803 Down 0.09255755 0.72287071 miR-382-5p −0.1556784 Down 0.57309052 0.93390911 miR-24-1-5p −0.1555473 Down 0.0214993 0.53734625 let-7g-5p −0.1552145 Down 0.0589026 0.64832335 miR-141-3p −0.1552026 Down 0.2682486 0.82860446 miR-410-3p −0.1546221 Down 0.67560231 0.95648223 miR-4484 −0.1524305 Down 0.15907323 0.75988515 miR-29c-3p −0.1520516 Down 0.27357655 0.83107769 miR-143-3p −0.1517947 Down 0.5724,9896 0.93390911 let-7a-5p −0.1495243 Down 0.03567474 0.59871978 miR-185-5p −0.1490736 Down 0.02508744 0.55568816 miR-320e −0.1469298 Down 0.28061814 0.83108541 miR-1202 −0.1447347 Down 0.21813416 0.78840757 miR-340-3p −0.143247 Down 0.33859524 0.85489649 miR-331-3p −0.1428154 Down 0.14940403 0.75393664 miR-5196-5p −0.1427908 Down 0.00386774 0.34045223 miR-20a-3p −0.142275 Down 0.0577224 0.64832335 miR-628-5p −0.1421981 Down 0.13722984 0.75376261 miR-4443 −0.1404353 Down 0.3747999 0.86499071 miR-381-3p −0.1404195 Down 0.62104792 0.94829596 miR-628-3p −0.1400851 Down 0.16633836 0.76915081 miR-221-5p −0.1390408 Down 0.13217561 0.74892227 miR-4291 −0.1371731 Down 0.22098446 0.79098893 miR-4323 −0.1368585 Down 0.31730879 0.84917098 miR-30e-3p −0.136426 Down 0.09755372 0.73085631 miR-29c-5p −0.1359778 Down 0.16497145 0.76915081 miR-409-5p −0.1346939 Down 0.30048022 0.83872374 miR-200b-3p −0.1335934 Down 0.19960532 0.77997491 miR-15b-5p −0.133299 Down 0.14604441 0.75376261 miR-6763-5p −0.1325476 Down 0.05511816 0.64056718 miR-200c-3p −0.1319846 Down 0.1147884 0.74226488 miR-652-5p −0.131862 Down 0.03226253 0.59871978 miR-103a-3p −0.130681 Down 0.15260836 0.75393664 miR-548am-5p −0.1286466 Down 0.14518387 0.75376261 miR-192-5p −0.1269884 Down 0.43987942 0.88952595 miR-107 −0.1264259 Down 0.17675208 0.77062416 miR-29b-3p −0.1262268 Down 0.44560284 0.88952595 miR-548u −0.1254266 Down 0.00389978 0.34045223 miR-181c-3p −0.1246398 Down 0.38653847 0.86961208 miR-130b-3p −0.1231865 Down 0.2852138 0.83289761 miR-320d −0.123168 Down 0.24893553 0.80715125 miR-4788 −0.1222474 Down 0.07291182 0.68406327 miR-484 −0.1219113 Down 0.12894549 0.74892227 miR-323a-3p −0.1208658 Down 0.26817005 0.82860446 miR-505-3p −0.1202214 Down 0.3035112 0.83872374 miR-4749-3p −0.1199575 Down 0.15869565 0.75988515 miR-15a-3p −0.1183105 Down 0.03708407 0.59871978 miR-320a −0.1182161 Down 0.30403967 0.83872374 miR-642b-5p −0.1180559 Down 0.1856993 0.77677007 miR-6071 −0.1133686 Down 0.00487931 0.35828046 miR-17-5p −0.1130513 Down 0.37019062 0.8625475 miR-1307-3p −0.1127969 Down 0.05488986 0.64056718 miR-181a-3p −0.1127909 Down 0.56807995 0.9303065 miR-363-3p −0.1111045 Down 0.60447515 0.94188142 miR-6778-5p −0.1085699 Down 0.1468648 0.75376261 miR-6766-3p −0.1081158 Down 0.11137142 0.74226488 miR-370-3p −0.1079054 Down 0.24840514 0.80715125 miR-3912-5p −0.1077988 Down 0.11473463 0.74226488 miR-374a-5p −0.107496 Down 0.38675744 0.86961208 miR-548as-3p −0.1065386 Down 0.00778767 0.40696367 miR-627-5p −0.1061354 Down 0.02263304 0.53734625 miR-625-3p −0.1049602 Down 0.16316836 0.76802692 miR-766-3p −0.1048801 Down 0.39499968 0.87310741 miR-362-3p −0.1026706 Down 0.45364747 0.89093879 miR-487b-3p −0.1012303 Down 0.74956338 0.97742837 miR-95-3p −0.1007765 Down 0.35316418 0.8588192 miR-545-3p −0.1005441 Down 0.06176618 0.65102084 miR-423-3p −0.0987889 Down 0.38194551 0.86612247 miR-19b-3p −0.0986038 Down 0.37474451 0.86499071 miR-548aj-3p −0.0984553 Down 0.02308954 0.53734625 miR-6724-5p −0.0973248 Down 0.05694408 0.64832335 miR-1299 −0.097018 Down 0.09632474 0.73085631 miR-1306-5p −0.0968363 Down 0.10062764 0.73085631 miR-302a-3p −0.0965015 Down 0.02612879 0.55959148 miR-376b-3p −0.096174 Down 0.33797387 0.85489649 miR-3916 −0.0958997 Down 0.01268218 0.45268334 miR-1287-5p −0.0954145 Down 0.06349926 0.65539395 miR-374b-5p −0.0947825 Down 0.09792616 0.73085631 miR-31-5p −0.0934179 Down 0.81129553 0.99064883 miR-4422 −0.0933521 Down 0.07548529 0.68726073 miR-4682 −0.0928982 Down 0.12060406 0.74226488 miR-3680-3p −0.0922184 Down 0.00244716 0.34045223 miR-191-5p −0.0910243 Down 0.12444248 0.74454632 miR-361-3p −0.090964 Down 0.52487295 0.91825968 miR-26b-5p −0.0908946 Down 0.21108356 0.78263372 miR-6727-5p −0.0908214 Down 0.0219247 0.53734625 miR-6888-3p −0.0908122 Down 0.02132992 0.53734625 miR-320b −0.0903495 Down 0.4217382 0.8823614 miR-106a-3p −0.0896953 Down 0.0139619 0.46600109 miR-4639-3p −0.0890044 Down 0.02945662 0.59616058 miR-548L −0.0889439 Down 0.01327019 0.46067162 miR-6856-3p −0.088886 Down 0.01234784 0.44695703 miR-3192-3p −0.0887498 Down 0.01718806 0.53220869 miR-550a-3p −0.088041 Down 0.36796855 0.86195734 miR-125b-1-3p −0.0877112 Down 0.24414246 0.80715125 miR-4668-3p −0.0875502 Down 0.02816443 0.59258245 miR-6082 −0.0865329 Down 0.15071067 0.75393664 miR-574-3p −0.0854029 Down 0.47265855 0.89396011 miR-3606-5p −0.0844866 Down 0.02275562 0.53734625 miR-148a-5p −0.0830521 Down 0.01814262 0.53734625 miR-664a-3p −0.0828903 Down 0.55610772 0.9268462 miR-6826-5p −0.0828478 Down 0.28421782 0.83193599 miR-541-5p −0.0823983 Down 0.03891282 0.59871978 miR-6884-3p −0.0821635 Down 0.15347294 0.75393664 miR-3124-5p −0.082068 Down 0.11585557 0.74226488 miR-3616-3p −0.0817705 Down 0.0990518 0.73085631 miR-618 −0.0814829 Down 0.01137484 0.43937422 miR-629-5p −0.081454 Down 0.32855493 0.85489649 miR-6784-5p −0.0814167 Down 0.03529383 0.59871978 miR-425-5p −0.0813279 Down 0.23355464 0.80019585 miR-4261 −0.0812625 Down 0.16684807 0.76915081 miR-4482-3p −0.0811715 Down 0.04757793 0.61412501 miR-1291 −0.0810705 Down 0.14627622 0.75376261 miR-3158-3p −0.0800994 Down 0.07766898 0.68910078 miR-590-3p −0.0792172 Down 0.03519026 0.59871978 miR-26a-1-3p −0.0791541 Down 0.17249915 0.77062416 miR-6813-5p −0.0783623 Down 0.02180293 0.53734625 let-7c-3p −0.0778908 Down 0.11832515 0.74226488 miR-150-5p −0.07768 Down 0.49872051 0.91032268 miR-5190 −0.0774762 Down 0.15597493 0.75633126 miR-20b-5p −0.0772418 Down 0.1460428 0.75376261 miR-4270 −0.0770622 Down 0.38633037 0.86961208 miR-31-3p −0.076925 Down 0.2362799 0.80380192 miR-5088-3p −0.0768011 Down 0.09382537 0.72555728 miR-6511b-3p −0.076708 Down 0.02162468 0.53734625 miR-196a-5p −0.0765723 Down 0.27611079 0.83108541 miR-1249-3p −0.0757546 Down 0.2545288 0.81031406 miR-9-5p −0.0751537 Down 0.12923434 0.74892227 miR-6516-5p −0.0745078 Down 0.06014748 0.64832335 miR-4687-5p −0.0740003 Down 0.30255863 0.83872374 miR-6731-5p −0.0739289 Down 0.03193883 0.59871978 miR-141-5p −0.0733955 Down 0.07957451 0.68910078 miR-4780 −0.073278 Down 0.1286269 0.74892227 miR-374b-3p −0.0731784 Down 0.06692731 0.65890175 miR-369-5p −0.0731604 Down 0.57647798 0.93390911 let-7d-3p −0.0728777 Down 0.17184823 0.77062416 miR-661 −0.0728391 Down 0.03624906 0.59871978 miR-649 −0.0727858 Down 0.04419742 0.61412501 miR-4298 −0.0724915 Down 0.47222756 0.89396011 miR-4683 −0.0724638 Down 0.0546774 0.64056718 miR-5692c −0.0723209 Down 0.08824084 0.71090581 miR-4688 −0.0717924 Down 0.1290666 0.74892227 miR-874-5p −0.0713546 Down 0.03569465 0.59871978 miR-654-3p −0.0712607 Down 0.77258369 0.98440262 miR-6772-5p −0.0708382 Down 0.14810668 0.75376261 miR-361-5p −0.0707358 Down 0.46871632 0.89396011 miR-526b-3p −0.0697051 Down 0.14424637 0.75376261 miR-515-5p −0.069631 Down 0.03156651 0.59871978 miR-7156-5p −0.0690574 Down 0.1545765 0.75393664 miR-6886-3p −0.0685914 Down 0.12854264 0.74892227 miR-16-2-3p −0.0684503 Down 0.21995732 0.78841048 miR-4731-3p −0.0681986 Down 0.30047948 0.83872374 miR-548ax −0.0680894 Down 0.14111828 0.75376261 miR-296-3p −0.0678209 Down 0.10482914 0.74226488 miR-664a-5p −0.0677982 Down 0.45251254 0.89093879 miR-655-5p −0.0677311 Down 0.10801005 0.74226488 miR-4680-3p −0.0675655 Down 0.21604469 0.7853205 miR-6749-5p −0.0673259 Down 0.33082272 0.85489649 miR-337-3p −0.06711 Down 0.55060733 0.92349191 miR-504-3p −0.0669662 Down 0.14725315 0.75376261 miR-758-3p −0.0665848 Down 0.62687523 0.9498341 miR-937-3p −0.0665441 Down 0.05297921 0.63842356 miR-548av-3p −0.066494 Down 0.08687757 0.70907074 miR-5572 −0.0661791 Down 0.05630095 0.64832335 miR-140-5p −0.0660041 Down 0.45375538 0.89093879 miR-1227-5p −0.0658486 Down 0.03691231 0.59871978 miR-4776-5p −0.0657861 Down 0.03971689 0.59871978 miR-548ab −0.0655982 Down 0.10855319 0.74226488 miR-15b-3p −0.0655518 Down 0.07743768 0.68910078 miR-6796-3p −0.0655189 Down 0.12426931 0.74454632 miR-1233-5p −0.0654842 Down 0.15416195 0.75393664 miR-922 −0.0653003 Down 0.08895039 0.71411286 miR-5189-3p −0.0649979 Down 0.15558891 0.75588563 miR-4267 −0.0648969 Down 0.03895436 0.59871978 miR-7162-5p −0.0647263 Down 0.18856121 0.77997491 miR-33a-3p −0.0642384 Down 0.11657237 0.74226488 miR-942-5p −0.0637306 Down 0.06524443 0.65598378 miR-134-5p −0.0637176 Down 0.44938568 0.88964976 miR-539-5p −0.0636818 Down 0.46151992 0.89396011 miR-28-3p −0.063576 Down 0.19253465 0.77997491 miR-6081 −0.0634098 Down 0.2394534 0.80380192 miR-7854-3p −0.0633369 Down 0.08215352 0.69839839 miR-624-5p −0.0632708 Down 0.26163925 0.81989814 miR-2115-3p −0.0630218 Down 0.07815829 0.68910078 miR-4652-3p −0.063004 Down 0.24882332 0.80715125 miR-489-5p −0.0629817 Down 0.05217839 0.63253996 miR-212-5p −0.062839 Down 0.19944415 0.77997491 miR-1273e −0.0623133 Down 0.10094184 0.73085631 miR-134-3p −0.0622349 Down 0.17724741 0.77062416 miR-6875-3p −0.0617556 Down 0.1375524 0.75376261 miR-219a-5p −0.0616904 Down 0.2533948 0.80998089 miR-493-3p −0.0611597 Down 0.09806579 0.73085631 miR-6881-5p −0.0609269 Down 0.09484994 0.72765477 miR-125a-3p −0.0608378 Down 0.21286419 0.78263372 miR-4439 −0.0605871 Down 0.1233437 0.74454632 miR-4730 −0.0605398 Down 0.06998566 0.67187824 miR-383-3p −0.0604946 Down 0.09662856 0.73085631 miR-548ay-3p −0.060446 Down 0.03093749 0.59781471 miR-3180-3p −0.0601756 Down 0.07181798 0.68344128 miR-10b-3p −0.0598146 Down 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miR-6500-5p 0.00709102 Up 0.88389959 0.99898712 miR-7109-3p 0.00715258 Up 0.86817229 0.99898712 miR-761 0.00725141 Up 0.80469338 0.99064883 miR-3685 0.00726365 Up 0.79280404 0.98676309 miR-4714-3p 0.00729509 Up 0.85892014 0.99898712 miR-6866-5p 0.00730567 Up 0.84621505 0.99654281 miR-4526 0.00733506 Up 0.76375104 0.98140055 miR-4436b-5p 0.00741513 Up 0.88151895 0.99898712 miR-3153 0.0074168 Up 0.76947281 0.98237037 miR-4772-3p 0.0075411 Up 0.81766753 0.99127826 miR-3663-5p 0.00762725 Up 0.80974872 0.99064883 miR-3065-5p 0.00770806 Up 0.73065485 0.97193735 miR-3141 0.00776054 Up 0.90607938 0.99898712 miR-1292-3p 0.00776917 Up 0.81851928 0.99127826 miR-4756-5p 0.00780377 Up 0.79286606 0.98676309 miR-7976 0.00782671 Up 0.8670542 0.99898712 miR-3140-3p 0.0078855 Up 0.79720547 0.98759926 miR-4441 0.00799964 Up 0.70676444 0.96360966 miR-211-3p 0.00803022 Up 0.87470817 0.99898712 miR-3174 0.00810481 Up 0.75961032 0.98140055 miR-6720-5p 0.00818865 Up 0.84626862 0.99654281 miR-4304 0.0082361 Up 0.79025258 0.98667434 miR-1264 0.00861208 Up 0.8411249 0.99654281 miR-3912-3p 0.00863814 Up 0.87433044 0.99898712 miR-4506 0.00870046 Up 0.90739398 0.99898712 miR-1284 0.008722 Up 0.79085029 0.98667434 miR-5681b 0.00876411 Up 0.8584131 0.99898712 miR-548aa 0.00890056 Up 0.84798854 0.99654281 miR-4269 0.00892899 Up 0.81451596 0.99122915 miR-7158-5p 0.00894845 Up 0.86729561 0.99898712 miR-452-5p 0.00895862 Up 0.85771099 0.99898712 miR-4490 0.00898673 Up 0.73250027 0.9725372 miR-656-5p 0.00904604 Up 0.74755094 0.97721563 miR-6506-5p 0.00904757 Up 0.67559786 0.95648223 miR-4755-5p 0.0090802 Up 0.76114498 0.98140055 miR-1273a 0.00909625 Up 0.70701626 0.96360966 miR-6878-5p 0.00916874 Up 0.83254408 0.9955233 miR-6840-5p 0.00917447 Up 0.78853145 0.98667434 miR-888-5p 0.00930898 Up 0.6728992 0.95648223 miR-4494 0.00934109 Up 0.65694105 0.95321673 miR-3689b-3p 0.00939617 Up 0.78293583 0.98667434 miR-6804-5p 0.00939724 Up 0.65264057 0.95321673 miR-4698 0.00943298 Up 0.84142941 0.99654281 miR-3134 0.00954703 Up 0.73284844 0.9725372 miR-6880-5p 0.00956249 Up 0.84058856 0.99654281 miR-6764-3p 0.00958155 Up 0.7778236 0.985258 miR-6840-3p 0.00960503 Up 0.80087863 0.98907164 miR-596 0.0096344 Up 0.6972447 0.96239183 miR-6823-3p 0.0096698 Up 0.83033428 0.99448905 miR-3200-5p 0.00979753 Up 0.82584554 0.99340905 miR-6828-3p 0.00989754 Up 0.76984199 0.98237037 miR-4783-3p 0.00995837 Up 0.73689972 0.97354829 miR-4670-5p 0.01004604 Up 0.76449957 0.98140055 miR-136-3p 0.01006505 Up 0.85730812 0.99898712 miR-365a-5p 0.01010965 Up 0.70048463 0.96268515 miR-4748 0.01013589 Up 0.79150405 0.98667434 miR-4742-3p 0.0101833 Up 0.77805094 0.985258 miR-4520-5p 0.0102179 Up 0.8304177 0.99448905 miR-1180-3p 0.01021945 Up 0.66003638 0.95397723 miR-3691-5p 0.01022264 Up 0.72226246 0.96627512 miR-2681-5p 0.01028915 Up 0.71152528 0.96505269 miR-203a-5p 0.01029073 Up 0.74476166 0.97605174 miR-4536-5p 0.01032611 Up 0.79814929 0.98759926 miR-548aj-5p 0.01034554 Up 0.76659882 0.98213308 miR-3150a-3p 0.01034608 Up 0.72387137 0.96691758 miR-4433a-3p 0.01036148 Up 0.83417748 0.99622199 miR-450a-5p 0.01036798 Up 0.93799632 0.99898712 miR-5096 0.01038371 Up 0.71906775 0.96505269 miR-4762-5p 0.01039264 Up 0.77610745 0.985258 miR-6809-5p 0.01040392 Up 0.79202691 0.98667434 miR-3682-5p 0.01042188 Up 0.81098701 0.99064883 miR-1295b-3p 0.01043015 Up 0.71909568 0.96505269 miR-4444 0.01045387 Up 0.7631112 0.98140055 miR-888-3p 0.01047353 Up 0.76818709 0.98237037 miR-302d-3p 0.01049923 Up 0.80356561 0.99063213 miR-4520-3p 0.01052429 Up 0.61164525 0.94386479 miR-365b-5p 0.01054114 Up 0.79167801 0.98667434 miR-490-5p 0.01063911 Up 0.69008095 0.96036263 miR-4796-3p 0.01068572 Up 0.69512286 0.96185982 miR-6883-5p 0.01079249 Up 0.65690962 0.95321673 miR-6766-5p 0.01097063 Up 0.73980817 0.97402999 miR-5707 0.01098079 Up 0.7204253 0.96558066 miR-3187-5p 0.01105233 Up 0.61637057 0.94741169 miR-7846-3p 0.0110547 Up 0.76558774 0.98147681 miR-6777-5p 0.0111177 Up 0.65793259 0.95321673 miR-4258 0.01123609 Up 0.84001222 0.99654281 miR-4797-5p 0.01124647 Up 0.68924997 0.96036263 miR-181a-5p 0.01129006 Up 0.93201014 0.99898712 miR-4734 0.0113266 Up 0.68320782 0.95853044 miR-5682 0.01146077 Up 0.54685586 0.92261663 miR-5589-5p 0.01146606 Up 0.68330492 0.95853044 miR-1296-3p 0.01148509 Up 0.74748801 0.97721563 miR-489-3p 0.01149592 Up 0.76884233 0.98237037 miR-4496 0.01149734 Up 0.74960999 0.97742837 miR-7978 0.01150772 Up 0.78322993 0.98667434 miR-676-3p 0.01153637 Up 0.80272434 0.99063213 miR-4650-3p 0.01157133 Up 0.5971788 0.93868471 miR-216a-5p 0.0116056 Up 0.6784294 0.95648223 miR-5197-3p 0.01164863 Up 0.76952426 0.98237037 miR-3132 0.01168148 Up 0.75960371 0.98140055 miR-3150b-5p 0.011704 Up 0.78040012 0.98667434 miR-668-5p 0.01170815 Up 0.66036011 0.95397723 miR-5092 0.01171057 Up 0.65400126 0.95321673 miR-6834-5p 0.01173243 Up 0.63699015 0.95096807 miR-3179 0.01173464 Up 0.70553052 0.96360966 miR-582-3p 0.01180101 Up 0.65549123 0.95321673 miR-4781-3p 0.01182106 Up 0.71425667 0.96505269 miR-4502 0.01188395 Up 0.66321265 0.95510802 miR-3149 0.01193411 Up 0.75330525 0.97975429 miR-4712-5p 0.01193425 Up 0.77741809 0.985258 miR-3130-3p 0.01198522 Up 0.72070737 0.96558066 miR-4473 0.01201285 Up 0.61156537 0.94386479 miR-3142 0.01202439 Up 0.82632704 0.99340905 miR-1910-5p 0.01204555 Up 0.86979935 0.99898712 miR-5008-5p 0.01210927 Up 0.67184466 0.95648223 miR-6769a-3p 0.01231759 Up 0.67377095 0.95648223 miR-550b-2-5p 0.0123235 Up 0.6803527 0.95756103 miR-132-5p 0.01239979 Up 0.62785584 0.9498341 miR-377-5p 0.01243349 Up 0.73963553 0.97402999 miR-3612 0.01246368 Up 0.75708145 0.98140055 miR-3908 0.01253284 Up 0.71684988 0.96505269 miR-34c-5p 0.01254468 Up 0.70448188 0.96360966 miR-6765-5p 0.01255238 Up 0.67419733 0.95648223 miR-4745-3p 0.01256461 Up 0.69898791 0.96268515 miR-4738-3p 0.01276161 Up 0.59320033 0.93770773 miR-4638-3p 0.01277387 Up 0.59292589 0.93770773 miR-1914-5p 0.01282594 Up 0.73045802 0.97193735 miR-129-5p 0.01283002 Up 0.63258914 0.95096807 miR-544a 0.01283799 Up 0.74617411 0.9764091 miR-579-5p 0.01285453 Up 0.62994592 0.95065239 miR-3914 0.01286086 Up 0.62464601 0.94934372 miR-651-3p 0.01287047 Up 0.69538348 0.96185982 miR-6084 0.01293593 Up 0.65583838 0.95321673 miR-181b-3p 0.01306301 Up 0.78935621 0.98667434 miR-410-5p 0.01310405 Up 0.51984245 0.91632037 miR-323b-5p 0.01310415 Up 0.69390838 0.96137172 miR-7849-3p 0.0131112 Up 0.61849336 0.94829596 miR-597-3p 0.01311716 Up 0.71900872 0.96505269 miR-124-5p 0.0131234 Up 0.79377874 0.98694309 miR-363-5p 0.01318634 Up 0.76210555 0.98140055 miR-3934-3p 0.01322045 Up 0.67932933 0.9566446 miR-3687 0.01324644 Up 0.59548597 0.93868471 miR-3167 0.01333017 Up 0.63645436 0.95096807 miR-4710 0.01333306 Up 0.52798647 0.92119547 miR-4307 0.01336258 Up 0.70485276 0.96360966 miR-4775 0.01343595 Up 0.54052103 0.9213181 miR-3928-5p 0.01351781 Up 0.80368404 0.99063213 miR-92a-1-5p 0.01356483 Up 0.75096762 0.97770354 miR-517-5p 0.01361653 Up 0.66420343 0.95510802 miR-1292-5p 0.01366842 Up 0.63710706 0.95096807 miR-202-3p 0.01377676 Up 0.62199514 0.94868101 miR-8056 0.01404629 Up 0.65642876 0.95321673 miR-3936 0.01405122 Up 0.69131766 0.96077402 miR-4661-3p 0.01406232 Up 0.53649807 0.9213181 miR-4481 0.01414048 Up 0.65872097 0.95321673 miR-1298-5p 0.01414814 Up 0.70116334 0.96268515 miR-429 0.01419675 Up 0.57850214 0.93436563 miR-4774-3p 0.0142617 Up 0.64602929 0.95321673 miR-548ad-5p 0.01427071 Up 0.56433017 0.93029412 miR-4472 0.01428134 Up 0.54467602 0.92261663 miR-4517 0.01429999 Up 0.65536784 0.95321673 miR-99b-3p 0.01433655 Up 0.54153182 0.92167998 miR-4644 0.01436547 Up 0.64547146 0.95321673 miR-1250-5p 0.01443761 Up 0.53908047 0.9213181 miR-372-3p 0.0144946 Up 0.58151827 0.93436563 miR-656-3p 0.01455139 Up 0.80755313 0.99064883 miR-4640-3p 0.01456831 Up 0.78150428 0.98667434 miR-105-3p 0.01458433 Up 0.55080673 0.92349191 miR-4498 0.01461732 Up 0.60334631 0.94089807 miR-3688-5p 0.01464264 Up 0.61124878 0.94386479 miR-6801-5p 0.01464637 Up 0.60580933 0.94188142 miR-4656 0.01466241 Up 0.89012295 0.99898712 miR-6856-5p 0.01469675 Up 0.5891102 0.93675929 miR-5586-5p 0.01477128 Up 0.67846969 0.95648223 miR-6756-3p 0.0148236 Up 0.84494113 0.99654281 miR-6729-3p 0.01488382 Up 0.76047908 0.98140055 miR-4531 0.01488447 Up 0.59076862 0.93675929 miR-3937 0.01490706 Up 0.73739196 0.97354829 miR-3607-5p 0.01492801 Up 0.68988789 0.96036263 miR-4744 0.01496713 Up 0.58205836 0.93436563 miR-1537-3p 0.01497413 Up 0.74459697 0.97605174 miR-5584-5p 0.015004 Up 0.6644876 0.95510802 miR-4778-5p 0.01507405 Up 0.70791484 0.96360966 miR-6852-3p 0.01514938 Up 0.63082411 0.95086097 miR-938 0.01520606 Up 0.65801777 0.95321673 miR-3177-5p 0.01524698 Up 0.51696969 0.91376348 miR-3199 0.0152907 Up 0.69019057 0.96036263 miR-4477a 0.01533614 Up 0.6204992 0.94829596 miR-1185-2-3p 0.01534462 Up 0.71296587 0.96505269 miR-6509-3p 0.01541891 Up 0.73653953 0.97354829 miR-6884-5p 0.01546598 Up 0.44533113 0.88952595 miR-4765 0.01550301 Up 0.49293956 0.90695643 miR-502-5p 0.01550968 Up 0.80976632 0.99064883 miR-5588-3p 0.0155201 Up 0.65535348 0.95321673 miR-3191-3p 0.01552654 Up 0.55550861 0.9264485 miR-4716-3p 0.01552688 Up 0.88286114 0.99898712 miR-4426 0.01555663 Up 0.60204571 0.93953261 miR-4311 0.01562945 Up 0.66332341 0.95510802 miR-6730-3p 0.01579544 Up 0.63661012 0.95096807 miR-4796-5p 0.01579621 Up 0.81253151 0.99064883 miR-378j 0.01582298 Up 0.59044664 0.93675929 miR-4276 0.01582809 Up 0.49987739 0.91121111 miR-5091 0.01587546 Up 0.51631719 0.91376348 miR-622 0.01587548 Up 0.65431659 0.95321673 miR-4477b 0.01595427 Up 0.67510492 0.95648223 miR-4480 0.01605291 Up 0.68121945 0.95825614 miR-6730-5p 0.0160569 Up 0.6543226 0.95321673 miR-4653-5p 0.01607326 Up 0.60565483 0.94188142 miR-3934-5p 0.01611412 Up 0.64022393 0.95096807 miR-301b-5p 0.01621443 Up 0.61120826 0.94386479 miR-4642 0.01624775 Up 0.68349862 0.95853044 miR-6871-3p 0.01627526 Up 0.41542735 0.8804535 miR-211-5p 0.01631686 Up 0.78984502 0.98667434 miR-448 0.01636933 Up 0.68645874 0.96036263 miR-548ai 0.01646598 Up 0.76498329 0.98147681 miR-6502-3p 0.01660247 Up 0.75312865 0.97975429 miR-4430 0.01667698 Up 0.87860394 0.99898712 miR-6740-3p 0.01668376 Up 0.71732029 0.96505269 miR-4727-5p 0.01668725 Up 0.59607151 0.93868471 miR-5004-3p 0.01670733 Up 0.5998042 0.93953261 miR-5684 0.01673479 Up 0.78501761 0.98667434 miR-5002-3p 0.01677134 Up 0.64641587 0.95321673 miR-1203 0.01680127 Up 0.66528781 0.95557578 miR-369-3p 0.01686971 Up 0.60979891 0.94386479 miR-200a-3p 0.01701242 Up 0.52452216 0.91825968 miR-375 0.01706379 Up 0.55983417 0.9276427 miR-30d-5p 0.01708292 Up 0.7998693 0.98830004 miR-3689a-3p 0.01718387 Up 0.49300838 0.90695643 miR-1909-5p 0.0172932 Up 0.65705658 0.95321673 miR-4750-3p 0.01735663 Up 0.74220642 0.97419331 miR-3675-3p 0.01737469 Up 0.80972313 0.99064883 miR-765 0.01737509 Up 0.69856279 0.96268515 miR-6775-5p 0.01746273 Up 0.71605815 0.96505269 miR-497-3p 0.0174979 Up 0.50358715 0.91147569 miR-4500 0.01753437 Up 0.62783916 0.9498341 miR-139-3p 0.01757692 Up 0.86938452 0.99898712 miR-3194-3p 0.01763165 Up 0.50079992 0.91121111 miR-4679 0.01782269 Up 0.5908509 0.93675929 miR-27a-5p 0.01792569 Up 0.56305474 0.92970327 miR-1296-5p 0.01793662 Up 0.58790108 0.93675929 miR-4755-3p 0.01795334 Up 0.54032429 0.9213181 miR-671-5p 0.01798175 Up 0.91512111 0.99898712 miR-520e 0.01806457 Up 0.70204427 0.96268515 miR-670-3p 0.01811048 Up 0.63264444 0.95096807 miR-3929 0.01811785 Up 0.52196244 0.91732227 miR-936 0.01818701 Up 0.50295729 0.91147569 miR-203b-5p 0.0183307 Up 0.54804896 0.92261663 miR-6776-3p 0.01834543 Up 0.70605908 0.96360966 miR-3611 0.01837621 Up 0.62549396 0.9498341 miR-376b-5p 0.0184051 Up 0.58970873 0.93675929 miR-148b-5p 0.01843913 Up 0.62829493 0.9498341 miR-153-3p 0.01844682 Up 0.60505783 0.94188142 miR-4795-5p 0.01849838 Up 0.62346004 0.94925841 miR-551b-5p 0.01851548 Up 0.47290103 0.89396011 miR-6083 0.0185183 Up 0.49043732 0.90695643 miR-6829-5p 0.0185316 Up 0.68941596 0.96036263 miR-1245b-3p 0.01889982 Up 0.59437657 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0.03657297 0.59871978 miR-500a-5p 0.07386426 Up 0.15142982 0.75393664 miR-2053 0.07413253 Up 0.1346475 0.75226974 miR-451b 0.07445664 Up 0.06375711 0.65542311 miR-6800-3p 0.07499934 Up 0.1424747 0.75376261 miR-5581-5p 0.07511844 Up 0.21009407 0.78263372 miR-642b-3p 0.07598197 Up 0.36915419 0.86195734 miR-371a-3p 0.07664063 Up 0.08711322 0.70907074 miR-548ae-3p 0.07679238 Up 0.21885155 0.78840757 miR-4753-3p 0.077048 Up 0.00651694 0.40231598 miR-4653-3p 0.07749411 Up 0.12336065 0.74454632 miR-550a-5p 0.07848802 Up 0.24791286 0.80715125 miR-509-3p 0.07856046 Up 0.03093376 0.59781471 miR-3607-3p 0.07871814 Up 0.6208883 0.94829596 miR-3620-3p 0.07893846 Up 0.04506553 0.61412501 miR-3943 0.07894053 Up 0.02604419 0.55959148 miR-6502-5p 0.07908038 Up 0.20157974 0.77997491 miR-3151-3p 0.07967298 Up 0.12119654 0.74226488 miR-1255a 0.07973658 Up 0.05181195 0.63253996 miR-34c-3p 0.07994349 Up 0.09180651 0.72153737 miR-1252-3p 0.08011389 Up 0.03880862 0.59871978 miR-186-3p 0.08026808 Up 0.03610748 0.59871978 miR-6891-5p 0.08058981 Up 0.28582416 0.83289761 miR-3646 0.0809914 Up 0.41406383 0.8804535 miR-7110-5p 0.08143144 Up 0.17902444 0.77062416 miR-6824-3p 0.08146995 Up 0.12843883 0.74892227 miR-135a-3p 0.08192344 Up 0.26560242 0.82438552 miR-144-3p 0.08254493 Up 0.81458209 0.99122915 miR-3195 0.08270457 Up 0.24420862 0.80715125 miR-548az-5p 0.08303471 Up 0.0395986 0.59871978 miR-3945 0.08394863 Up 0.12433998 0.74454632 miR-3139 0.08450308 Up 0.02320834 0.53734625 miR-6791-5p 0.08464489 Up 0.4183558 0.88201345 miR-1915-3p 0.08517208 Up 0.53746958 0.9213181 miR-542-5p 0.08526668 Up 0.46783284 0.89396011 miR-519e-3p 0.08567418 Up 0.11759491 0.74226488 miR-5585-3p 0.08579912 Up 0.46178841 0.89396011 miR-378g 0.08622678 Up 0.05316056 0.63842356 miR-548h-5p 0.08641971 Up 0.18294233 0.77350881 miR-6895-3p 0.08645486 Up 0.02529787 0.55568816 miR-8060 0.08676058 Up 0.09109285 0.72012996 miR-6738-3p 0.08676132 Up 0.07990351 0.68910078 miR-8061 0.08705854 Up 0.01130452 0.43937422 miR-7162-3p 0.08711663 Up 0.02294984 0.53734625 miR-6737-3p 0.08722144 Up 0.25604062 0.81102287 miR-6867-5p 0.08729181 Up 0.05940578 0.64832335 miR-1267 0.08783125 Up 0.01084837 0.43937422 miR-3591-3p 0.08842998 Up 0.00854575 0.40696367 miR-6515-5p 0.08897001 Up 0.04215507 0.60118096 let-7c-5p 0.08921252 Up 0.50684609 0.912181 miR-377-3p 0.08929848 Up 0.61601294 0.94741169 miR-602 0.08990339 Up 0.08499877 0.70240141 miR-4691-5p 0.09233981 Up 0.06685589 0.65890175 miR-876-3p 0.09288635 Up 0.04792887 0.61412501 miR-23b-5p 0.0930458 Up 0.03197789 0.59871978 miR-548am-3p 0.09494395 Up 0.00255307 0.34045223 miR-96-5p 0.09510759 Up 0.13818989 0.75376261 miR-614 0.09555571 Up 0.02218303 0.53734625 miR-29a-3p 0.09570771 Up 0.31794301 0.84917098 miR-532-5p 0.09574706 Up 0.53567007 0.9213181 miR-135a-5p 0.09654651 Up 0.0829293 0.69839839 miR-193a-5p 0.09719116 Up 0.09703079 0.73085631 miR-4497 0.09803222 Up 0.17758974 0.77062416 miR-4433a-5p 0.09851921 Up 0.03675037 0.59871978 miR-1277-3p 0.09875703 Up 0.03483406 0.59871978 miR-6507-3p 0.09886526 Up 0.09969864 0.73085631 miR-890 0.09952414 Up 0.0034835 0.34045223 miR-1234-3p 0.09955079 Up 0.36352269 0.8588192 miR-6851-3p 0.09975676 Up 0.19181651 0.77997491 miR-8084 0.09976723 Up 0.00359751 0.34045223 miR-4725-5p 0.09978071 Up 0.21267843 0.78263372 miR-3155b 0.09979122 Up 0.00278283 0.34045223 miR-501-5p 0.10032761 Up 0.39061255 0.87281803 miR-4507 0.10099259 Up 0.31915037 0.84972893 miR-181b-5p 0.10183856 Up 0.35637515 0.8588192 miR-4800-5p 0.10217379 Up 0.22684006 0.79102241 miR-1973 0.10318636 Up 0.27355317 0.83107769 miR-876-5p 0.10322575 Up 0.00648836 0.40231598 miR-4689 0.10347357 Up 0.15000646 0.75393664 miR-4485-5p 0.10376712 Up 0.42637587 0.88249386 miR-1470 0.1042914 Up 0.14840618 0.75376261 miR-4536-3p 0.10440502 Up 0.00797512 0.40696367 miR-4478 0.10495 Up 0.0747843 0.68406327 miR-4310 0.1058934 Up 0.10095486 0.73085631 miR-98-3p 0.10626554 Up 0.02112264 0.53734625 miR-575 0.1064784 Up 0.35501009 0.8588192 miR-15a-5p 0.10652983 Up 0.35983269 0.8588192 miR-6858-5p 0.10799872 Up 0.14672844 0.75376261 miR-224-3p 0.10808806 Up 0.11591039 0.74226488 miR-3118 0.10852694 Up 0.0138673 0.46600109 miR-660-5p 0.10883293 Up 0.46688213 0.89396011 miR-663a 0.10974097 Up 0.28324328 0.83193599 miR-1238-5p 0.11034519 Up 0.01534139 0.49284222 miR-4665-3p 0.11195401 Up 0.49477477 0.90848159 miR-7704 0.11225656 Up 0.09124377 0.72012996 miR-4312 0.1126684 Up 0.06065803 0.64832335 miR-4466 0.1128636 Up 0.44582227 0.88952595 miR-3074-3p 0.1131561 Up 0.01597018 0.50670832 miR-6131 0.11373774 Up 0.11445403 0.74226488 miR-3941 0.1148302 Up 0.00122462 0.26227331 miR-4449 0.11599411 Up 0.33275425 0.85489649 miR-342-5p 0.11633261 Up 0.46550933 0.89396011 miR-548c-3p 0.11721243 Up 0.0425739 0.60118096 miR-638 0.11790044 Up 0.10193756 0.73589757 miR-937-5p 0.11821584 Up 0.16926304 0.77062416 miR-6769b-3p 0.1190295 Up 0.00061825 0.15302397 miR-483-3p 0.12066504 Up 0.06664188 0.65890175 miR-6752-3p 0.1209839 Up 0.11746481 0.74226488 miR-3164 0.12126773 Up 0.02485249 0.55568816 miR-425-3p 0.12135184 Up 0.07479447 0.68406327 miR-6515-3p 0.12361515 Up 0.29894341 0.83872374 miR-3125 0.12402533 Up 0.15451361 0.75393664 miR-1825 0.12797268 Up 0.05740226 0.64832335 miR-6797-3p 0.13035638 Up 0.16601533 0.76915081 miR-1181 0.13038863 Up 0.12071581 0.74226488 miR-6821-5p 0.13109406 Up 0.37417957 0.86499071 miR-1238-3p 0.13295731 Up 0.08977201 0.71650331 miR-6890-3p 0.13318201 Up 0.00293306 0.34045223 miR-1260a 0.13337208 Up 0.32936032 0.85489649 miR-8072 0.13401883 Up 0.00902604 0.40696367 miR-6880-3p 0.13423449 Up 0.01863114 0.53734625 miR-6734-5p 0.13476722 Up 0.02094573 0.53734625 miR-5580-3p 0.13672314 Up 0.05083706 0.62512553 miR-1304-3p 0.1371615 Up 0.00400137 0.34045223 miR-199b-5p 0.13739765 Up 0.5988803 0.93906184 miR-4465 0.13988188 Up 0.35513979 0.8588192 miR-4746-3p 0.14518648 Up 0.02208845 0.53734625 miR-6759-3p 0.14532219 Up 0.08313556 0.69839839 let-7b-5p 0.14614295 Up 0.35081789 0.8588192 miR-4634 0.14754824 Up 0.14617632 0.75376261 miR-4505 0.14761153 Up 0.04246345 0.60118096 miR-502-3p 0.14780681 Up 0.1566901 0.75715578 miR-4649-3p 0.14788706 Up 0.01102337 0.43937422 miR-6124 0.15010733 Up 0.20156221 0.77997491 miR-4687-3p 0.15063161 Up 0.33744806 0.85489649 let-7f-1-3p 0.15074119 Up 0.05525242 0.64056718 miR-636 0.15213534 Up 0.00198209 0.32405862 miR-762 0.15570984 Up 0.08053749 0.68993782 miR-1228-3p 0.15582107 Up 0.16159926 0.76484365 let-7i-5p 0.1564672 Up 0.04506864 0.61412501 miR-6803-5p 0.15706346 Up 0.31237204 0.8475125 miR-6893-5p 0.15994903 Up 0.11245159 0.74226488 miR-33b-3p 0.16368374 Up 0.15801165 0.75988515 miR-34b-5p 0.16407042 Up 0.04167753 0.60118096 miR-513b-5p 0.16733719 Up 0.14386933 0.75376261 miR-3665 0.16739733 Up 0.40603336 0.87475982 miR-4785 0.16909089 Up 0.01306086 0.45981375 miR-140-3p 0.17052129 Up 0.039837 0.59871978 miR-3196 0.17113537 Up 0.21620731 0.7853205 miR-191-3p 0.17179396 Up 0.04487927 0.61412501 miR-4515 0.17261046 Up 0.01939174 0.53734625 miR-125b-5p 0.17326977 Up 0.58039482 0.93436563 miR-4284 0.17499241 Up 0.13111512 0.74892227 miR-6717-5p 0.17647607 Up 0.07006357 0.67187824 miR-4455 0.17661528 Up 0.05721903 0.64832335 miR-4767 0.17813392 Up 0.00704444 0.40231598 miR-7107-5p 0.17892282 Up 0.25114209 0.80715125 miR-1260b 0.17907235 Up 0.14017212 0.75376261 miR-3198 0.17929237 Up 0.02123337 0.53734625 miR-1290 0.18406083 Up 0.03967176 0.59871978 miR-4485-3p 0.1846673 Up 0.07340574 0.68406327 miR-6503-3p 0.18979698 Up 0.28804023 0.83439474 miR-582-5p 0.19045558 Up 0.62677845 0.9498341 miR-3940-5p 0.19057902 Up 0.08648205 0.70907074 miR-6879-5p 0.19101714 Up 0.02231673 0.53734625 miR-6125 0.19106394 Up 0.1196758 0.74226488 miR-3162-3p 0.19525376 Up 0.06057967 0.64832335 miR-4442 0.19537199 Up 0.02357392 0.54093726 miR-4669 0.19873977 Up 0.05792698 0.64832335 miR-8063 0.19905207 Up 0.33357986 0.85489649 miRNABrightCorner30 0.20171928 Up 0.3490045 0.8588192 miR-378d 0.20715078 Up 0.16934925 0.77062416 dmr_285 0.20740733 Up 0.13348728 0.74892227 miR-4281 0.21053809 Up 0.14469165 0.75376261 miR-3653-3p 0.21583612 Up 0.20986195 0.78263372 dmr_31a 0.21728525 Up 0.18051196 0.77062416 miR-6800-5p 0.21733255 Up 0.1072548 0.74226488 miR-8485 0.21842128 Up 0.13247253 0.74892227 miR-532-3p 0.22031918 Up 0.17750992 0.77062416 miR-29b-1-5p 0.22084105 Up 0.22324885 0.79102241 miR-6069 0.22136576 Up 0.00413241 0.34045223 miR-574-5p 0.22143706 Up 0.09257117 0.72287071 miR-4739 0.22479676 Up 0.46193717 0.89396011 miR-7975 0.22883797 Up 0.21088885 0.78263372 miR-4721 0.2307112 Up 0.0365265 0.59871978 miR-1207-5p 0.23240555 Up 0.24200969 0.80715125 miR-4530 0.23343011 Up 0.13226628 0.74892227 miR-362-5p 0.24215656 Up 0.28398808 0.83193599 miR-6767-5p 0.24557824 Up 0.00430298 0.34045223 miR-5006-5p 0.24665791 Up 0.10970319 0.74226488 miR-940 0.24920107 Up 0.1206625 0.74226488 miR-4512 0.24979984 Up 0.00061516 0.15302397 miR-5100 0.25235575 Up 0.34779581 0.8588192 miR-6740-5p 0.25563327 Up 0.00409229 0.34045223 miR-6088 0.25633403 Up 0.04560842 0.61412501 miR-3651 0.25657361 Up 0.09007374 0.71668583 miR-4428 0.26039231 Up 0.01098536 0.43937422 miR-619-5p 0.26233591 Up 0.02890641 0.59616058 miR-4299 0.26378168 Up 0.16313713 0.76802692 miR-1268a 0.26900448 Up 0.02969275 0.59616058 miR-4763-3p 0.27411287 Up 0.15236304 0.75393664 miR-4728-5p 0.27540238 Up 0.00902596 0.40696367 miR-1273g-3p 0.28401482 Up 0.00853108 0.40696367 miR-6780b-5p 0.28445951 Up 0.00201749 0.32405862 miR-193a-3p 0.29191057 Up 0.22860566 0.79102241 miR-4697-5p 0.29577233 Up 0.02066387 0.53734625 miR-338-3p 0.30407515 Up 0.33547234 0.85489649 miR-4713-3p 0.31190821 Up 0.00441411 0.34045223 miR-6127 0.31227553 Up 0.02937864 0.59616058 miR-3663-3p 0.32622686 Up 0.17739186 0.77062416 miR-197-5p 0.32730894 Up 0.01165849 0.43937422 miR-1225-5p 0.32794342 Up 0.04237249 0.60118096 miR-4667-5p 0.33094713 Up 0.11216581 0.74226488 miR-6089 0.33321123 Up 0.06419436 0.65598378 miR-642a-3p 0.33705253 Up 0.0354651 0.59871978 miR-3960 0.34205792 Up 0.21934296 0.78840757 miR-6087 0.34742973 Up 0.01824337 0.53734625 miR-4286 0.35393924 Up 0.15460101 0.75393664 miR-6875-5p 0.35408709 Up 0.00825659 0.40696367 miR-664b-5p 0.35527207 Up 0.00544933 0.36854655 miR-513a-5p 0.37891789 Up 0.00367033 0.34045223 miR-4459 0.38291314 Up 0.03613368 0.59871978 miR-424-5p 0.39379877 Up 0.17613337 0.77062416 miR-6090 0.40130574 Up 0.11481495 0.74226488 miR-365a-3p 0.40351876 Up 0.01344372 0.46067162 miR-1246 0.4191497 Up 0.0080711 0.40696367 miR-6785-5p 0.43652493 Up 0.02101025 0.53734625 miR-6869-5p 0.44434072 Up 0.00970313 0.42994906 miR-34a-5p 0.45746932 Up 0.20090282 0.77997491 miR-6132 0.46392014 Up 0.02511952 0.55568816 miR-451a 0.5157088 Up 0.15065058 0.75393664 miR-494-3p 0.52730171 Up 0.00892038 0.40696367 miR-21-3p 0.55990013 Up 0.21932847 0.78840757 miR-7641 0.60997261 Up 5.26×10^−5 0.06753368 miR-378a-3p 0.65466586 Up 0.07470725 0.68406327 miR-378i 0.67902917 Up 0.06336176 0.65539395 miR-3130-5p 0.7469237 Up 0.31234802 0.8475125 miR-4516 0.75421011 Up 0.12234989 0.74454632 miR-6769b-5p 1.16196437 Up 0.00062927 0.15302397 [192]Open in a new tab Figure 6. [193]Figure 6 [194]Open in a new tab The circRNA-lncRNA-miRNA-mRNA network. The round nodes represent DEcircRNAs, the rhombic nodes represent DElncRNAs, the v-type nodes represent DEmRNAs, the square nodes represent DEmiRNAs. The up or down-regulated genes are represented in red and green, respectively. Hsa_circ_0002202 Inhibition Suppressed the IFN-I-Induced Inflammation To confirm our above discovery and conceive future study designs, we chose hsa_circ_0002202 with more miRNA targets for in vitro experiments. We first used the geNorm and normFinder algorithms to select the reference gene for normalization. As shown in [195]Supplementary Figure 1, β-actin was the most stable reference gene. Then, subcellular distribution analysis illustrated that hsa_circ_0002202 is mainly located in the cytoplasm in THP-1-derived macrophages, with the remaining proportion in the nucleus ([196]Figure 7A). Transfection of si-circ significantly decreased hsa_circ_0002202 expression in THP-1-derived macrophages ([197]Figure 7B). Afterward, qRT-PCR results showed that hsa_circ_0002202 knockdown significantly suppressed the expression of IFIT1, IFIH1, CXCL10, and iNOS under IFN-I stimulation, suggesting an inhibitory effect of hsa_circ_0002202 knockdown on IFN-I-induced inflammation ([198]Figure 7C). Figure 7. [199]Figure 7 [200]Open in a new tab Inhibition of hsa_circ_0002202 suppressed IFN-I-induced inflammation. (A) Subcellular distribution of hsa_circ_0002202 in the nucleus and cytoplasm in THP-1-derived macrophages. (B) qRT-PCR detection of hsa_circ_0002202 expression after transfection with si-NC or si-circ. (C) qRT-PCR detection of IFIT1, IFIH1, CXCL10, and iNOS expression under IFN-I stimulation after treatment with hsa_circ_0002202 siRNA. Data are presented as the mean ± SD of three experiments and analyzed using one-way ANOVA with Tukey’s post-test. *P<0.05, **P<0.01, compared with the si-NC group. Discussion Despite great efforts to find treatment strategies, T1DM is still a terrible threat to human health, and its prevalence is still rising worldwide. To better understand the exact mechanisms of T1DM and promote the discovery of new biomarkers, we analyzed the gene expression data from GEO public database. Furthermore, we established a circRNA-lncRNA-miRNA-mRNA ceRNA regulatory network in T1DM, which elucidated the underlying pathogenesis of T1DM. The post-transcriptional regulation of gene expression mediated by the ceRNA regulatory network during the diseases process has attracted wide attention from researchers. In diabetes and diabetic complications, the ceRNA regulatory network in pathophysiological processes has been widely reported. For example, lncRNA MT1P3 promoted p2y12 expression by sponging miR-126 to promote platelet activation and aggregation in type 2 diabetes.[201]^45 lncRNA H2k2/miR-449a/b/Trim11 signaling pathway promotes mesangial cell proliferation in diabetic nephropathy.[202]^46 Hsa_circ_010567/miR-141/TGF-β1 axis promotes myocardial fibrosis in diabetic mice.[203]^47 The complex interaction network of multiple factors may be more theoretically meaningful for revealing the internal mechanism of T1DM. But few studies focused on the ceRNA regulatory networks in T1DM. Meanwhile, previous studies on T1DM ceRNA regulatory networks only discussed the role of either lncRNA[204]^48 or circRNA,[205]^33 and did not consider both of them simultaneously. Therefore, this study was systematic and comprehensive for revealing the T1DM mechanism. In the current study, we identified 178 DEcircRNAs, 404 DElncRNAs, and 73 DEmRNAs from the [206]GSE133225 database. Meanwhile, we analyzed the miRNA chip [207]GSE133217 to construct the interaction network of circRNA, lncRNA, miRNA, and mRNA. This network suggested that circRNA and lncRNA play a central regulatory role in T1DM. One circRNA and lncRNA can be associated with multiple identical miRNAs to regulate more mRNAs synergistically. Among the circRNAs and lncRNAs, circRNA hsa_circ_0002202 and lncRNA [208]AL356740.2–201 (ENST00000601559.1) linked most miRNAs. Here, we selected hsa_circ_0002202 for the in vitro experiment verification. Hsa_circ_0002202 is formed from SMAD4A. A previous study has reported the oncogene role of circSAMD4A in osteosarcoma.[209]^49 Liu et al found that circSAMD4A acts as an adipogenesis promoting factor.[210]^50 In this study, we found that hsa_circ_0002202 was up-regulated in T1DM PBMCs samples, suggesting that hsa_circ_0002202 may take part in the T1DM procession. As the circRNAs show their sponge function in the cytoplasm,[211]^26 we detected the cellular localization of hsa_circ_0002202 in THP-1-derived macrophages. The results showed that hsa_circ_0002202 was mainly localized in the cytoplasm of THP-1-derived macrophage. Furthermore, we found that knockdown of hsa_circ_0002202 suppressed the IFN-I-induced inflammation, which was in line with the previous study.[212]^51 These findings suggested that hsa_circ_0002202 play an important role in T1DM, which will be verified by tissue sample experiments, cell lines experiments, and even animal model construction in future studies. The miRNAs in the T1DM-related ceRNA regulatory network are also important regulators in T1DM. In this study, we found that hsa_circ_0002207 could sponge miR-487a-3p, miR-576-5p, miR-326, miR-186-5p, and many other miRNAs. Among the miRNAs, miR-487a-3p is reported to be up-regulated in the PBMCs of T1DM patients.[213]^52 Increased expression of miR-326 was identified in PBMSCs[214]^53 and peripheral blood lymphocytes[215]^54 of patients with T1DM. Another study showed a decreased expression level of miR-326 in PBMCs of patients with T1DM.[216]^55 These same or opposite results may be related to the genetic or environmental factors of T1DM patients. Besides, some other miRNAs in the ceRNA network may be related to other autoimmune disorders, which have strong complications with T1DM. The pro-inflammatory cytokines promote the miR-455-3p expression and then cause the inflammatory β-cell failure.[217]^56 miR-31-5p, miR-665, miR-326, miR-224 are associated with inflammatory bowel disease.[218]^56–59 We will also conduct verification and analysis in future experimental studies to obtain more in-depth and comprehensive scientific conclusions. In the present study, the biological function and potential pathways of the DEcircRNAs and DElncRNAs were also analyzed. The enriched GO terms were mainly related to extracellular matrix components (ECM) and macrophage activation. The ECM contributes to islet inflammation and creates a permissive environment for immune cells to infiltrate the pancreatic islets and impair β-cell survival.[219]^60 Macrophages participate in interacting, directing, or restricting trafficking of the autoreactive-specific T cells into the islets via the IFN-I signaling during the development of T1DM.[220]^61 Thus, our in vitro experiments focused on macrophage inflammation, and the results indicated the anti–inflammatory effect of hsa_circ_0002202 inhibition. In terms of the KEGG pathway, the protein digestion and absorption were enriched, indicating that the activation of these genes was closely related to the T1DM progression. We also identified some genes associated with T1DM, including GREM2, RAPGEF5, C9orf152, SMKR1, SORBS1, HSPB8, CACNA2D2, SKOR1, and SLFNL1. Among these, SORBS1 and CACNA2D2 are previously reported to be related to diabetes. SORBS1, a human homologue for c-Cbl-associated protein (CAP), is an important adaptor protein in the insulin-signaling pathway, and its genetic polymorphism is related to insulin resistance.[221]^62 Meanwhile, another study showed that SORBS1 might be a new susceptibility gene for diabetic nephropathy.[222]^63 CACNA2D2 is the voltage-gated calcium channel auxiliary subunit alpha2delta2 gene that encodes a calcium channel protein,[223]^64 and Huang et al identified CACNA2D2 as a diabetes-related atherogenesis gene.[224]^65 Besides, GREM2 and HSPB8 are closely related to inflammatory response,[225]^66^,[226]^67 suggesting a regulatory role in the T1DM macrophages inflammation. These genes with special functions may be the latest molecular markers of T1DM and need further experimental verification. Despite the above results, there are still some limitations in the current study. First, the small sample size may affect the number of altered RNAs. Further studies based on a larger sample size should be performed to confirm our conclusions. Second, besides acting as miRNA sponges, circRNAs or lncRNAs can also regulate gene expression by affecting transcription.[227]^68^,[228]^69 At the same time, most of the results are obtained using bioinformatics analysis. Thus, experimental studies are needed to validate our results and further investigate the deeper mechanism. Third, the progress of T1DM is not only related to M1 macrophage activation induced exacerbation of inflammatory responses but also related to the absolute insulin deficiency caused by pancreatic β-cells destruction. This study only studies the former, and the effect of these differentially expressed genes on the latter needs further studies. Conclusions In conclusion, we identified differentially expressed circRNAs, lncRNAs, and mRNAs in the PBMCs from T1DM patients and healthy patients and established a T1DM-related circRNA-lncRNA-miRNA-mRNA ceRNA regulatory network for the first time. The construction of the ceRNA network can help to further analyze the interaction between ncRNAs and mRNAs and provide new insights into the molecular mechanisms in T1DM. The new ceRNA network in this study will contribute to the diagnosis and treatment of T1DM. Of course, our research findings are only the first step. In the follow-up experimental verification study, we will rely on multiple levels, including clinical tissue samples, cell line studies, and animal models, to analyze the internal function mechanism. Funding Statement There is no funding to report. Abbreviations BP, biological processes; CAP, c-Cbl-associated protein; CC, cellular components; circRNA, circular RNA; ceRNA, competitive endogenous RNA; DEcircRNAs, differentially expressed circRNAs; DElncRNAs, differentially expressed lncRNAs; DEGs, differentially expressed genes; DEmRNAs, differentially expressed mRNAs; ECM, extracellular matrix components; GEO, Gene Expression Omnibus; GO, Gene Ontology; IFN-I, type I interferon; KEGG, Kyoto Encyclopedia of Genes and Genomes; lncRNA, long non-coding RNA; miRNA, microRNA; MRE, miRNA response element; MF, molecular functions; ncRNA, non-coding RNA; PBMCs, peripheral blood mononuclear cells; PMA, phorbol 12-myristate 13-acetate; qRT-PCR, Quantitative real-time PCR; T1DM, Type 1 diabetes mellitus. Author Contributions Both authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. Disclosure The authors declare that they have no conflicts of interest for this work. References