Identification of Cooperative Gene Regulation Among Transcription Factors, LncRNAs, and MicroRNAs in Diabetic Nephropathy Progression

Abstract

The pathogenesis of diabetic nephropathy (DN) is accompanied by alterations in biological function and signaling pathways regulated through complex molecular mechanisms. A number of regulatory factors, including transcription factors (TFs) and non-coding RNAs (ncRNAs, including lncRNAs and miRNAs), have been implicated in DN; however, it is unclear how the interactions among these regulatory factors contribute to the development of DN pathogenesis. In this study, we developed a network-based analysis to decipher interplays between TFs and ncRNAs regulating progression of DN by combining omics data with regulatory factor-target information. To accomplish this, we identified differential expression programs of mRNAs and miRNAs during early DN (EDN) and established DN. We then uncovered putative interactive connections among miRNA-mRNA, lncRNA-miRNA, and lncRNA-mRNA implicated in transcriptional control. This led to the identification of two lncRNAs (MALAT1 and NEAT1) and the three TFs (NF-κB, NFE2L2, and PPARG) that likely cooperate with a set of miRNAs to modulate EDN and DN target genes. The results highlight how crosstalk among TFs, lncRNAs, and miRNAs regulate the expression of genes both transcriptionally and post-transcriptionally, and our findings provide new insights into the molecular basis and pathogenesis of progressive DN.

Long non‑coding RNA L13Rik promotes high glucose-induced mesangial cell hypertrophy and matrix protein expression by regulating miR-2861/CDKN1B axis

“…To prove that, a bioinformatics tool, miRDB ( ) ( Chen & Wang, 2020 ), was applied to predict miRNAs sponged by L13Rik, and 63 candidate miRNAs were identified ( Table S2 ). A previous study demonstrated that 86 miRNAs were dysexpressed in DN progression ( Table S3 ) ( Chen et al, 2020 ). Venn diagram analysis revealed that miR-2861 was the only miRNA that could be sponged by L13Rik and dysregulated in DN patients ( Fig.…”

Long non-coding RNA L13Rik promotes high glucose-induced mesangial cell injury by regulating miR-2861/CDKN1B axis

“…(Chen and Wang, 2020), was applied to predict miRNAs sponged by L13Rik, and 63 candidate miRNAs were identified (Supporting Table S1). A previous study has demonstrated that 86 miRNAs were dys-expressed in DN progression (Supporting Table S2) (Chen et al, 2020). Venn diagram analysis revealed that miR-2861 was the only miRNA that could be sponged by L13Rik and dy-sregulated in DN patients (Supporting Figure S3).…”

Genome-wide analysis of long noncoding RNAs as cis-acting regulators of transcription factor-encoding genes in IgA nephropathy

“…A few studies have illustrated the role of lncRNA in the development and progression of other diseases through regulation of TFs. Cooperative regulation among two lncRNAs (MALAT1 and NEAT1), three TFs (NF-κB, NFE2L2, and PPARG), and a set of miRNAs has been shown to regulate downstream differentially expressed genes (DEGs) [15]. The lncRNA MAGI2-AS3 has been shown to regulate ACY1 through interaction with the transcription factor HEY1 to prevent tumor growth and angiogenesis in clear cell renal cell carcinoma [16].…”