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The Chd4 helicase regulates chromatin accessibility and gene expression critical for β-cell function in vivo

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posted on 2023-03-13, 22:32 authored by Rebecca K. Davidson, Sukrati Kanojia, Wenting Wu, Tatsuyoshi Kono, Jerry Xu, Meredith Osmulski, Robert N. Bone, Nolan Casey, Carmella Evans-Molina, Emily K. Sims, Jason M. Spaeth

  

The transcriptional activity of Pdx1 is modulated by a diverse array of coregulatory factors that govern chromatin accessibility, histone modifications, and nucleosome distribution. We previously identified the Chd4 subunit of the Nucleosome Remodeling and Deacetylase complex as a Pdx1-interacting factor. To identify how loss of Chd4 impacts glucose homeostasis and gene expression programs in β-cells in vivo, we generated an inducible-β-cell-specific Chd4 knockout mouse model. Removal of Chd4 from mature islet β-cells rendered mutant animals glucose intolerant, in part due to defects in insulin secretion. We observed an increased ratio of immature:mature insulin granules in Chd4-deficient β-cells that correlated with elevated levels of proinsulin both within isolated islets and from plasma following glucose stimulation in vivo. RNA- and ATAC-Sequencing showed that lineage-labeled Chd4-deficient β-cells have alterations in chromatin accessibility and altered expression of genes critical for β-cell function, including MafA, Slc2a2, Chga, and Chgb. Knockdown of CHD4 from a human β-cell line revealed similar defects in insulin secretion and alterations in several β-cell-enriched gene targets. These results illustrate how critical Chd4 activities are in controlling genes essential for maintaining β-cell function.

Funding

This work was supported by grants from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (K01-DK115633, R03-DK127129 and R01-DK129287 to J.M.S., F31-DK128918 to R.K.D., R01-DK121929 and R01-DK133881 to E.K.S., R01-DK093954, R01-DK127236, and R01-DK127308-01 to C.E.-M.), the U.S. Department of Veterans Affairs Merit Award (I01-BX001733 to C.E.-M.), an award from the Ralph W. and Grace M. Showalter Research Trust and the Indiana University School of Medicine (J.M.S.), Bridge funding from the Wells Center for Pediatric Research (J.M.S.) and an Early Career Development Award from the Central Society for Clinical and Translational Research (J.M.S.).

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