353-OR: Chd3 Helicase Modulates Pancreatic ß-Cell Function in Absence of Chd4

Pdx1, an essential transcription factor during β-cell development, controls expression of genes required to maintain β-cell function through selective recruitment of transcriptional coregulators. We recently found that Chd4, a helicase within the Nucleosome Remodeling and Deacetylase (NuRD) complex, interacts with and modulates Pdx1 transcriptional activity in β-cells, in part by controlling chromatin accessibility. This investigation revealed that removing Chd4 from mature β-cells (Chd4^Δβ) led to increased levels of Chd3, an alternate helicase subunit of the NuRD complex. We uncovered that Pdx1 and Chd3 interact in the mature β-cell and their interactions are increased in Chd4^Δβ β-cells, leading us to question whether Chd3 alone influences β-cell function or compensates in the absence of Chd4. We therefore generated mouse models with tamoxifen-inducible, β-cell-specific deletions of Chd3 (Chd3^Δβ) and Chd3/Chd4 (Chd3/4^Δβ). Four weeks following Chd3 removal, Chd3^Δβ mice showed no changes in glucose homeostasis, whereas Chd3/4^Δβ mutants exhibited severe glucose intolerance. Chd3/4^Δβ mutants displayed elevated ad libitum fed blood glucose levels, reduced β-cell mass, and insulin release in response to glucose was severely compromised, indicating a much more severe phenotype than Chd4^Δβ mutants. Further investigation revealed an increase in β-cell apoptosis and aberrant expression of glucagon in lineage labeled Chd3/4-deficient β-cells. These data suggest that Chd3 compensates for loss of Chd4, and loss of both subunits leads to β-cell demise and loss of identity. Future efforts are focused on evaluating gene expression and chromatin accessibility changes in Chd3/4^Δβ β-cells and the impact the diabetes milieu has on Pdx1:Chd3 interaction in β-cells of T2D mouse models and human donors with T2D.