CHD4 and NKX2.2 Cooperate to Regulate Beta Cell Function by Repressing Non-Beta Cell Gene Programs

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. To characterize the roles of CHD4 in β cells, we generated Chd4 βKO mice. Deletion of Chd4 substantially impaired the function of β cells. The Chd4 βKO mice became diabetic due to the disruption of islet integrity, calcium signaling and downregulation of essential β cell regulatory genes. We also discovered CHD4 and NKX2.2 are required to cooperatively bind at and repress non-beta cell genes, including Kcnj5, the gene that encodes the GIRK4 potassium channel in β cells. Aberrant upregulation of GIRK4 causes impaired glucose-stimulated insulin secretion. 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.