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The role of p300 transcriptional coactivators in pancreatic beta cells Wong, Chi Kin


Studies on genetic forms of diabetes have been pivotal in understanding how genetic mutations impair pancreatic β cell function. We identified a patient who presented with early-onset diabetes similar to known monogenic forms of diabetes. The patient carries a microdeletion that removes a copy of EP300, a gene that encodes the transcriptional coactivator p300. EP300 mutations cause Rubinstein-Taybi syndrome, a rare genetic condition that has been associated with early-onset glucose dysregulation. Whether and how p300 loss may affect β cell function in vivo was not clear. Here, we show that expression of p300 regulates β cell development and function in vivo. By deleting p300 at different developmental stages in mouse β cells, we demonstrate that p300 is required for the proliferation and proper maturation of developing β cells. β cell development requires p300 to acetylate histone H3K27 across the genome and to coactivate transcription. In mature β cells, p300 maintains insulin granule biosynthesis and secretion. To regulate these processes transcriptionally, p300 and NeuroD1/Nkx6.1/Pdx1 co-occupy loci that are critical for β cell function, including insulin. In addition to the mouse studies, we have identified three additional probands who developed hyperinsulinism associated with their rare, potentially gain-of-function EP300 variants. Our data demonstrate a critical role of p300 as a transcriptional coactivator and a histone acetyltransferase in β cells. Taken together, our human data highlight the relevance of p300 to the pathogenesis of genetic forms of diabetes, and our mouse data provide mechanistic insights on how p300 deficiency may lead to glucose dysregulation.

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