Journal Article Preprint Epublish 1 citation
PubMed: 40667117 DOI: 10.1101/2025.06.16.659956
The Chromatin Remodeler Protein CHD4 Cooperates With NKX2.2 to Regulate Pancreatic Beta Cell Integrity.
bioRxiv
Authors: Dylan K Sarbaugh, Thais Gaia Oliveira, Michelle A Guney, Victoria M Hoelscher, Christopher J Hill, Cole R Michel, Kristen L Wells, Richard K P Benninger, Lori Sussel
Affiliations
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
- School of Pharmacy, Mass Spectrometry Facility, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
Abstract
NKX2.2 is a transcription factor that regulates pancreatic islet beta (β) cell identity and function; however, cofactor proteins that modulate the functional activity of NKX2.2 in β cells are relatively unexplored. An unbiased proteomics screen identified chromodomain helicase DNA-binding protein 4 (CHD4) as an NKX2.2 interacting partner. CHD4 is a nucleosome remodeler that directs the appropriate differentiation, maturation and function of many cell types by activating or repressing genes. To characterize the NKX2.2-dependent and independent roles of CHD4 in β cells, we generated Chd4 βKO mice. Deletion of Chd4 substantially impaired the maturation and function of β cells. The Chd4 βKO mice were diabetic as early as 3 weeks of age due to the disruption of islet integrity, impaired glucose-stimulated insulin secretion and calcium signaling, and downregulation of essential β cell regulatory genes. These studies demonstrate that CHD4 is an essential transcriptional cofactor of NKX2.2 that is required for the proper maturation and function of pancreatic β cells.
MeSH
Cells, Genes, Insulin-Secreting Cells, Chromatin