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

Abstract

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 β-cells in vivo, we generated an inducible-β-cell-specific Chd4 knockout mouse model. Removal of Chd4 from mature islet β-cells rendered mutant animals glucose intolerant, in part due to defects in insulin secretion. We observed an increased ratio of immature:mature insulin granules in Chd4-deficient β-cells that correlated with elevated levels of proinsulin both within isolated islets and from plasma following glucose stimulation in vivo. RNA- and ATACSequencing showed that lineage-labeled Chd4-deficient β-cells have alterations in chromatin accessibility and altered expression of genes critical for β-cell function, including MafA, Slc2a2, Chga, and Chgb. Knockdown of CHD4 from a human β-cell line revealed similar defects in insulin secretion and alterations in several β-cell-enriched gene targets. These results illustrate how critical Chd4 activities are in controlling genes essential for maintaining β-cell function. Article Highlights Pdx1:Chd4 interactions were previously shown to be compromised in β-cells from human donors with type 2 diabetes. β-cell-specific removal of Chd4 impairs insulin secretion and leads to glucose intolerance in mice. Expression of key β-cell functional genes and chromatin accessibility are compromised in Chd4-deficient β-cells. Chromatin remodeling activities enacted by Chd4 are essential for β-cell function under normal physiological conditions.

Dynamic regulation of pancreatic β cell function and gene expression by the SND1 coregulator in vitro

“…The SWI/SNF chromatin remodeling complex was shown to control pancreatic progenitor cell proliferation and regulate insulin production by permitting PDX1 association with the Ins2 enhancer 14 . Furthermore, the CHD4 subunit of the NuRD complex was found to regulate glucose homeostasis in vivo and MafA expression by controlling MafA Region 3 enhancer accessibility 15 . Here our focus is on interrogating the role of the SND1 coregulator on controlling gene expression and β cell function in vitro .…”