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

• Published in: Diabetes (New York, N.Y.) Vol. 72; no. 6; pp. 746 - 757
• Main Authors: Davidson, Rebecca K, Kanojia, Sukrati, Wu, Wenting, Kono, Tatsuyoshi, Xu, Jerry, Osmulski, Meredith, Bone, Robert N, Casey, Nolan, Evans-Molina, Carmella, Sims, Emily K, Spaeth, Jason M
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.06.2023
• Subjects: Animals; Beta cells; Chromatin; Chromatin - genetics; Diabetes Mellitus, Type 2 - genetics; DNA helicase; DNA Helicases - genetics; Gene Expression; Glucose; Granule cells; Histones; Homeostasis; Humans; Insulin; Insulin secretion; Mi-2 Nucleosome Remodeling and Deacetylase Complex - genetics; Mice; Mice, Knockout; Transposase
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db22-0939

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-to-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 sequencing and assay for transposase-accessible chromatin with sequencing 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. 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.