The role of m6A and m6Am RNA modifications in the pathogenesis of diabetes mellitus

Abstract

The rapidly developing research field of epitranscriptomics has recently emerged into the spotlight of researchers due to its vast regulatory effects on gene expression and thereby cellular physiology and pathophysiology. N⁶-methyladenosine (m⁶A) and N⁶,2'-O-dimethyladenosine (m⁶Am) are among the most prevalent and well-characterized modified nucleosides in eukaryotic RNA. Both of these modifications are dynamically regulated by a complex set of epitranscriptomic regulators called writers, readers, and erasers. Altered levels of m⁶A and also several regulatory proteins were already associated with diabetic tissues. This review summarizes the current knowledge and gaps about m⁶A and m⁶Am modifications and their respective regulators in the pathophysiology of diabetes mellitus. It focuses mainly on the more prevalent type 2 diabetes mellitus (T2DM) and its treatment by metformin, the first-line antidiabetic agent. A better understanding of epitranscriptomic modifications in this highly prevalent disease deserves further investigation and might reveal clinically relevant discoveries in the future.

Keywords: RNA; T2DM; diabetes; epigenetics; epitranscriptomics; m6A; m6Am; type 2 diabetes mellitus.

Figure 1

Basic overview of m⁶A and m⁶Am epitranscriptomics. ALKBH5, AlkB family member 5; FTO, fat mass and obesity-associated; IGF2BP1-3, insulin-like growth factor 2 mRNA binding proteins 1-3; METTL3, methyltransferase-like 3; METTL14, methyltransferase-like 14; WTAP, Willms’ tumor 1-associating protein; YTHDC1-2, YTH domain-containing protein 1-2; YTHDF1-3, YTH domain-containing family proteins 1-3.

Figure 2

m⁶A and m⁶Am regulations in pancreatic islets of T2DM patients. ALKBH5, AlkB family member 5; FTO, fat mass and obesity-associated; HNRNPC, heterogeneous nuclear ribonucleoprotein C; IGF2BP2-3, insulin-like growth factor 2 mRNA binding proteins 2-3; m⁶A, N⁶-methyladenosine; METTL3, methyltransferase-like 3; METTL14, methyltransferase-like 14; T2DM, type 2 diabetes mellitus; WTAP, Willms’ tumor 1-associating protein; YTHDC1, YTH domain-containing protein 1; YTHDF1-3, YTH domain-containing family proteins 1-3.

Figure 3

Different epitranscriptomic regulations in DCM on T1DM and T2DM mouse hearts. ALKBH5, AlkB family member 5; FTO, fat mass and obesity-associated; m⁶A, N⁶-methyladenosine; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

Figure 4

Summary of epitranscriptomic regulations in diabetic tissues. ALKBH5, AlkB family member 5; DCM, diabetic cardiomyopathy; DN, diabetic nephrophathy; DR, diabetic retinopathy; FTO, fat mass and obesity-associated; HFD, high-fat diet; HNRNPC, heterogeneous nuclear ribonucleoprotein C; IGF2BP2-3, insulin-like growth factor 2 mRNA binding proteins 2-3; m⁶A, N⁶-methyladenosine; METTL14, methyltransferase-like 14; METTL3, methyltransferase-like 3; MTC, multicomponent methyltransferase complex; NAFLD, non-alcoholic fatty liver disease; SNPs, single-nucleotide polymorphisms; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; WTAP, Willms’ tumor 1-associating protein; YTHDC1, YTH domain-containing protein 1; YTHDF1-3, YTH domain-containing family proteins 1-3.