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 anti-inflammatory 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.
Marpadga A. Reddy, Vishnu Amaram, Sadhan Das, Vinay Singh Tanwar, Rituparna Ganguly, Mei Wang, Linda Lanting, Linxiao Zhang, Maryam Abdollahi, Zhuo Chen, Xiwei Wu, Sridevi Devaraj, Rama Natarajan