1733-P: Evaluating the Role of Chd3 Helicase Subunit on ß-Cell Function

Evaluating the role of Chd3 helicase subunit on β-cell function

Pancreatic β-cells play a crucial role in maintaining whole-body glucose homeostasis by secreting insulin upon increased blood glucose levels. To develop effective therapies to combat hyperglycemia, it is of vital importance to understand how β-cells function normally and the mechanisms driving their dysfunction in settings of diabetes. Pdx1, an essential transcription factor involved in β-cell development and function, dynamically recruits coregulators to drive gene expression programs. Recently, Pdx1 was shown to interact with Chd4, a helicase of Nucleosome Remodeling and Deacetylase (NuRD) complex within pancreatic β-cells. Chd4 was found to regulate insulin secretion, modulate expression of β-cell functional genes by modifying chromatin accessibility. We discovered that Chd4 removal from mature β-cells (Chd4^Δβ) increased Chd3 levels, an alternate Chd subunit of the NuRD complex. This led us to evaluate whether Chd3 alone plays a role in β-cell function and/or does it compensate in absence of Chd4. To investigate this possibility, we generated tamoxifen inducible, β-cell-specific Chd3 (Chd3^Δβ) and Chd3/Chd4 double knockout (Chd3/4^Δβ) mouse models. Whereas 4-weeks following Chd3 removal, Chd3^Δβ mice did not display glucose intolerance, the Chd3/4^Δβ mutants were profoundly glucose intolerant with elevated ad libitum fed blood glucose levels and near complete loss of insulin secretion in response to glucose, a phenotype much more severe than Chd4^Δβ mutants previously characterized. This data suggests Chd3 plays a pertinent role in the absence of Chd4 within the β-cell. Current efforts are focused on determining the insulin secretion capacity of Chd3/4^Δβ islets and evaluating gene expression and chromatin accessibility of Chd3/Chd4^Δβ β-cells.