H3K4 Methylation in β-cells Prevents Transcriptional Downregulation and Variance Associated with Type 2 Diabetes

Abstract

Pancreatic {beta}-cells control glucose homeostasis via regulated production and secretion of insulin. This function arises from a highly specialized gene expression program which is established during development and then sustained, with limited flexibility, in terminally differentiated {beta}-cells. Dysregulation of this program is seen in type 2 diabetes (T2D) but mechanisms that preserve gene expression or underlie its dysregulation in mature {beta}-cells are not well resolved. Here we show that trithorax group-dependent histone H3 lysine 4 trimethylation (H3K4me3) maintains expression of genes important for insulin biosynthesis and glucose-responsiveness in {beta}-cells. Transcriptional changes in H3K4me3-deficient {beta}-cells lead to severe hyperglycemia in adult mice. We show that H3K4me3 deficiency leads to a less active and more repressed epigenome profile, which locally correlates with gene expression deficits but does not globally reduce gene expression. Instead, developmentally regulated genes and genes in weakly active or suppressed states particularly rely on H3K4 methylation. We then show that H3K4me3 is re-organized in diabetic Leprdb/db mouse islets in favour of weakly active and disallowed genes at the expense of terminal {beta}-cell markers with broad H3K4me3 peaks. Our results point to key roles of H3K4me3 in maintaining mature {beta}-cell function and establishing a dysfunctional transcriptome in diabetic islets.