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bioRxiv · 10.1101/2025.06.16.659956

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

Sarbaugh, D. K.·Oliveira, T. G.·Guney, M. A.·Hoelscher, V. M.·Hill, C. J.·Michel, C. R.·Wells, K. L.·Benninger, R. K.·Sussel, L.
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Abstract

NKX2.2 is a transcription factor that regulates pancreatic islet beta ({beta}) cell identity and function; however, cofactor proteins that modulate the functional activity of NKX2.2 in {beta} 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 {beta} cells, we generated Chd4 {beta}KO mice. Deletion of Chd4 substantially impaired the function of {beta} cells. The Chd4 {beta}KO mice became diabetic due to the disruption of islet integrity, calcium signaling and downregulation of essential {beta} cell regulatory genes. We also discovered CHD4 is required to bind at and repress non-beta cell genes, including Kcnj5, the gene that encodes the GIRK4 potassium channel in {beta} 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 {beta} cells. Article HighlightsO_LINKX2.2 interacts with the Nucleosome Remodeling and Deacetylase (NuRD) complex through its interaction with CHD4. C_LIO_LIDeletion of CHD4 from developing pancreatic {beta} cells in mice causes diabetes due to a loss of islet integrity, disrupted calcium signaling and impaired insulin secretion. C_LIO_LIBeta cells lacking CHD4 inappropriately upregulate the GIRK4 potassium channel; inhibition of GIRK4 rescues the insulin secretion defect. C_LI

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Sarbaugh, D. K., Oliveira, T. G., Guney, M. A., Hoelscher, V. M., Hill, C. J., Michel, C. R., Wells, K. L., Benninger, R. K., Sussel, L.. 2025-06-17. The Chromatin Remodeler Protein CHD4 Cooperates With NKX2.2 to Regulate Pancreatic Beta Cell Integrity. https://doi.org/10.1101/2025.06.16.659956

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