Normal regulation of insulin gene transcription by glucose is essential for the maintenance of glucose homeostasis, and requires the beta-cell specific transcription factors Pdx-1, MafA and NeuroD1. However the exact mechanism(s) by which glucose increases insulin gene expression by modulating the function of these transcription factors remains unknown. We found that glucose regulates the DNA binding activity of Pdx-1 and that Pdx-1 is modified by acetylation. Furthermore, we discovered that glucose stimulates insulin gene transcription by causing hyperacetylation of histone H4 at the insulin promoter via the recruitment of the histone acetylase p300 by Pdx-1. Modification of core histones by acetylation has been shown to alter gene expression, but the mechanisms that direct histone acetylation to specific gene promoters are not well understood. Based on our preliminary data, we hypothesize that high blood glucose levels stimulate insulin gene transcription via modulation of histone H4 acetylation mediated by the beta-cell specific transcription factor Pdx-l. This hypothesis will be further investigated by addressing the following questions: 1) Is the glucose-regulated acetylation of Pdx-1 important for Pdx-1 activity and/or DNA binding? 2) What role do the histone acetyltransferases p300/CBP and GCN5/PCAF play in glucose regulation of insulin gene expression? 3) Do the beta-cell specific transcription factors MafA and NeuroD1 regulate insulin gene transcription by recruiting histone acetyltransferases? Although, most of the experiments will be carried out using the mouse insulinoma MIN6 cell line, the key findings will be confirmed using primary rat islets. Recent data indicate that defects in histone acetylation are associated with the pathogenesis of diabetes. Several of the diabetes-causing mutations in the MODY genes HNF-1alpha and HNF-4alpha interfere with their interaction with histone acetylases. Patients with Huntington's disease are prone to type II diabetes due to decreased insulin gene expression caused by degradation of histone acetylases. Information on how high blood glucose levels regulate beta-cell specific gene expression in the pancreas will help to understand how defects in this process result in diabetes. In addition, the data obtained will contribute to our understanding of Pdx-1, MafA and NeuroD1 function in the regulation of pancreas development and glucose-stimulated insulin gene transcription.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Sato, Sheryl M
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University of Kentucky
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Özcan, Sabire (2015) microRNAs in Pancreatic ?-Cell Physiology. Adv Exp Med Biol 887:101-17
Ozcan, Sabire (2014) Minireview: microRNA function in pancreatic ? cells. Mol Endocrinol 28:1922-33
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