The Chromatin Remodeler Protein CHD4 Cooperates With NKX2.2 to Regulate Pancreatic Beta Cell Integrity

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.