The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis

Abstract

Aims. Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in beta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysine demethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, we investigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4 methylation for islet function. Materials and Methods. We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain with knockout (KO) of the H3K4 demethylase KDM5B. Results. GSK-J4 administration failed to prevent the development of experimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabetic NOD to NODscid mice. KDM5B-KO mice were growth retarded with altered body composition, had low IGF-1 levels, and exhibited reduced insulin secretion. Interestingly, despite secreting less insulin, KDM5B-KO mice were able to maintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested by insulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged with high-fat diet, KDM5B-deficient mice displayed similar weight gain and insulin sensitivity as wild-type mice. Conclusion. Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity.

KDM4B facilitates colorectal cancer growth and glucose metabolism by stimulating TRAF6-mediated AKT activation

“…Recently, KDM3A, a demethylase that removes methyl form histone lysine H3K9, has been reported to promote urinary bladder cancer progression by enhancing glycolysis through coactivation of hypoxia inducible factor 1α [34]. KDM5B, another demethylase, has been reported to participate in the regulation of islet function and glucose homeostasis [35]. We also notice that the loss of KDM4B has been reported to result in metabolic dysfunction [17].…”

Epigenetics and Beyond: Targeting Histone Methylation to Treat Type 2 Diabetes Mellitus

“…H3K4me1/2/3, H3K36me2/3, and H3K79me2 are correlated with transcriptional activation ( Zheng et al, 2021 ). A genome-wide study of these modifications revealed that these modifications played critical roles in the specific promoters and enhancers of the islet and pathogenesis of diabetes ( Backe et al, 2019 ).…”

Pharmacoepigenetics in type 2 diabetes: is it clinically relevant?

“…For example, individuals with type 2 diabetes had higher DNMT3B levels in cultured myotubes [5] and decreased TET1 expression in adipose tissue [6] vs tissue from individuals without type 2 diabetes, while palmitate exposure decreased DNMT3A and DNMT1 expression in human pancreatic islets [11]. Several studies have further shown that inhibitors of HDACs and histone demethylases, or silencing and overexpressing those enzymes, impact beta cell function and insulin secretion [9,[46][47][48][49]. For example, DNA methylation is decreased, and expression of HDAC7 increased in pancreatic islets from donors with type 2 diabetes [49].…”