Both type 1 and type 2 diabetes are caused by inadequate functional beta-cells. Loss of beta-cells in diabetes is preceded by progressive beta-cell failure due to impaired beta-cell function and adaptive capacity, driven by cellular stress. While plenty of evidence suggests that beta-cell function and mass are co-regulated to dictate adaptive capacity, the molecular mechanisms that direct such co-regulation and are disrupted by cellular stress remain unclear. In the present study, we show that the CCCTC binding factor, CTCF is a novel epigenetic regulator of beta-cell functional maturity and mass. CTCF is a zinc finger protein that regulates 3D chromatin architecture and epigenetic stability towards transcriptional regulation, and plays an important role in cell differentiation, self-renewal, and survival. In addition, the levels of CTCF are sensitive to cellular-stress. Our data show that the beta-cell specific CTCF knockout mice (CTCF-BKO) become diabetic by 4-5 months of age, due to a progressive loss of beta-cell maturity and viability that mirrors evolving T2D. The CTCF-BKO mice have impaired glucose stimulated insulin secretion (GSIS), with metabolic, epigenetic, and gene expression profiles that resemble functionally immature neonatal beta-cells, around 1-2 months of age. This is followed by progressive loss of beta-cell mass due to p53 dependent apoptosis. In addition, mice with haplo-insufficiency of CTCF in their beta-cells display impaired GSIS and a deficit in the adaptive beta-cell expansion in response to high-fat diet challenge. Finally, we show that the CTCF program is disrupted in islets of diabetic mice. Taken together, these studies provide a novel insight into the epigenetic regulation of functional beta-cell mass and adaptive capacity in postnatal life.


S. Dhawan: None. T. Gurlo: None. J.K. Wang: None.

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