The Chd4 Helicase Regulates Chromatin Accessibility and Gene Expression Critical for β-Cell Function In Vivo

The transcriptional activity of Pdx1 is modulated by a diverse array of coregulatory factors that govern chromatin accessibility, histone modifications, and nucleosome distribution. We previously identified the Chd4 subunit of the nucleosome remodeling and deacetylase complex as a Pdx1-interacting factor. To identify how loss of Chd4 impacts glucose homeostasis and gene expression programs in beta-cells in vivo, we generated an inducible beta-cell-specific Chd4 knockout mouse model. Removal of Chd4 from mature islet beta-cells rendered mutant animals glucose intolerant, in part due to defects in insulin secretion. We observed an increased ratio of immature-to-mature insulin granules in Chd4-deficient beta-cells that correlated with elevated levels of proinsulin both within isolated islets and from plasma following glucose stimulation in vivo. RNA sequencing and assay for transposase-accessible chromatin with sequencing showed that lineage-labeled Chd4-deficient beta-cells have alterations in chromatin accessibility and altered expression of genes critical for beta-cell function, including MafA, Slc2a2, Chga, and Chgb. Knockdown of CHD4 from a human beta-cell line revealed similar defects in insulin secretion and alterations in several beta-cell-enriched gene targets. These results illustrate how critical Chd4 activities are in controlling genes essential for maintaining beta-cell function.