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

NKX2.2 is a transcription factor that regulates pancreatic islet 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 β-knockout (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 is required to bind at and repress non-β-cell genes, including Kcnj5, the gene that encodes the G protein-activated inward rectifier potassium channel 4 (GIRK4) 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. ARTICLE HIGHLIGHTS: NKX2.2 interacts with the nucleosome remodeling and deacetylase complex through its interaction with chromodomain helicase DNA-binding protein 4 (CHD4). Deletion of CHD4 from developing pancreatic β-cells in mice causes diabetes due to a loss of islet integrity, disrupted calcium signaling, and impaired insulin secretion. β-Cells lacking CHD4 inappropriately upregulate the G protein-activated inward rectifier potassium channel 4 (GIRK4) potassium channel; inhibition of GIRK4 rescues the insulin secretion defect.