MALAT1 and HOTAIR—Key Epigenetic Regulators in Diabetic Retinopathy

Introduction: With the increasing incidence of diabetic retinopathy (DR), the need for novel and specific therapy is essential. Genomic studies have identified several long non-coding RNAs (lncRNAs). However, majority of lncRNAs have not been characterized in DR. We examined the roles of lncRNAs MALAT1 and HOTAIR in DR.

Methods: Human retinal endothelial cells (HRECs) were cultured in 5 mM/L (NG) or in 25 mM/L (HG) glucose. RNA expressions of MALAT1, HOTAIR, and inflammatory and angiogenic cytokines were tested. HRECs were similarly examined following siRNA-mediated MALAT1 or HOTAIR knockdown, or treatment with histone (DZNep) and DNA methylation (52019-aza-dC) blockers. DNA methylation patterns and RNA-protein interactions were analyzed. Retinal tissues from Malat1 knockout (KO) and wild type (WT) mice with or without diabetes were examined. We further assessed MALAT1 a’nd HOTAIR in human diabetic and nondiabetic vitreous.

Results: HG caused upregulations of MALAT1, HOTAIR, IL-6, TNF-α, and VEGF-A transcripts in HRECs. HG increased binding of EZH2 (a PRC2 component) with MALAT1 and HOTAIR and evoked unique DNA methylation patterns in the MALAT1 and HOTAIR CpG regions. DZNep, 5-aza-dC and knockdown of MALAT1 or HOTAIR reduced mRNA expressions of IL-6, TNF-α, and VEGF-A. Similarly, diabetes-induced elevations of these inflammatory and angiogenic cytokines in the retina were prevented in the Malat1 KO mice. Furthermore, MALAT1 and HOTAIR levels were elevated in the diabetic vitreous.

Conclusions: Our findings allude to the importance of lncRNAs in influencing DR through epigenetic mediators. Understanding the role of lncRNAs may allow the development of better-targeted therapies in DR.