LncRNA DRAIR is downregulated in diabetic monocytes and modulates inflammatory phenotype via epigenetic mechanisms

Abstract

Long noncoding RNAs (lncRNAs) are increasingly implicated in the pathology of diabetic complications. Here we examined the role of lncRNAs in monocyte dysfunction and inflammation associated with human type 2 diabetes mellitus (T2D). RNA-seq analysis of CD14 + monocytes from patients with T2D versus healthy controls revealed downregulation of antiinflammatory and anti-proliferative genes along with several lncRNAs, including a novel divergent lncRNA DRAIR (Diabetes Regulated anti-inflammatory RNA) and its nearby gene CPEB2. High glucose and palmitic acid downregulated DRAIR in cultured CD14 + monocytes, whereas anti-inflammatory cytokines and monocyte-to-macrophage differentiation upregulated DRAIR via KLF4 transcription factor. DRAIR overexpression increased anti-inflammatory and macrophage differentiation genes but inhibited pro-inflammatory genes. Conversely, DRAIR knockdown attenuated anti-inflammatory genes, promoted inflammatory responses, and inhibited phagocytosis. DRAIR regulated target gene expression through interaction with chromatin, and inhibition of the repressive epigenetic mark H3K9me2 and its corresponding methyltransferase G9a. Mouse orthologous Drair and Cpeb2 were also downregulated in peritoneal macrophages from T2D db/db mice, and Drair knockdown in non-diabetic mice enhanced pro-inflammatory genes in macrophages. Thus, DRAIR modulates inflammatory phenotype of monocytes/macrophages via epigenetic mechanisms, and its downregulation in T2D may promote chronic inflammation. Augmentation of endogenous lncRNAs like DRAIR could serve as novel anti-inflammatory therapies for diabetic complications.

Emerging Role of Long Non-Coding RNAs in Diabetic Vascular Complications

“…Furthermore, DRAIR overexpression increased anti-inflammatory genes via inhibition of G9a recruitment and enrichment of repressive H3K9me2 at their promoters. These studies suggest that inhibition of DRAIR mediated epigenetic mechanisms via its downregulation and increased G9a could contribute to monocyte dysfunction and inflammation in diabetes (52).…”

“…Interestingly, evidence shows non-conserved lncRNAs harbor a significant number of SNPs associated with cardiometabolic traits than conserved lncRNAs, which can enhance our understanding of the roles of key SNPs and lncRNAs in driving disease pathogenesis (129). Moreover, lncRNAs expressed from syntenic gene loci often showed limited sequence conservation but had functional similarities in mice and humans (27,29,49,52). These studies demonstrate the importance of prioritizing not only conserved but also non-conserved lncRNAs for future studies.…”

Diabetes regulated anti-inflammatory lncRNA is overexpressed in triple-negative breast cancer and predicts chemoresistance and tumor recurrence

“…However, the role of most lncRNAs in TNBC is unclear. Diabetes regulated anti-inflammatory lncRNA (DRAIR) has been characterized as a critical player in type 2 diabetes mellitus [ 14 ]. However, its role in other human diseases is unclear.…”

Profile Screening of Differentially Expressed lncRNAs of Circulating Leukocytes in Type 2 Diabetes Patients and Differences From Type 1 Diabetes

“…Wang et al performed microarray analysis to screen out differential expressed mRNAs and lncRNAs between T2D patients and healthy control (14). Marpadga et al revealed downregulation of anti-inflammatory cytokines and antiproliferative genes, along with several lncRNAs, may promote chronic inflammation in T2D with RNA sequencing (15). Whether lncRNAs are involved blood cells or if they can be used to distinguish type 1 and 2 diabetes has not been explored.…”