Regulation of Insulin Gene Transcription by Histone Acetylation

Diabetes is a major risk factor for stroke, heart disease, limb amputations, kidney failure, and blindness. Most of the long-term complications associated with diabetes are due to chronic elevations in blood glucose levels (chronic hyperglycemia). Defects in insulin production in response to high blood glucose levels is a major contributing factor to hyperglycemia. Although, several of the transcription factors involved in glucose regulation of insulin gene expression in pancreatic beta cells have been identified, the exact molecular mechanism(s) by which glucose increases insulin gene expression by modulating the function of these specific transcriptions factors remains unknown. We hav,e recently discovered that glucose regulation of insulin gene expression is mediated by changes in histone acetylation via the beta-cell specific transcription factor Pdx-1, which recruits the histone acetylase p300 to the insulin gene promoter in a glucose-depedent manner. Based on these data, we hypothesize that high blood glucose levels stimulate insulin gene transcription by increasing histone H4 acetylation at the insulin gene promoter. We will test this hypothesis by pursuing the following specific aims: 1.Analysis of the role of histone modification in glucose regulation of beta-cell specific gene expression. 2. Determining the exact role of the transcription factors Pdx-1, Beta-2 and Ribe3b1 in the recruitment of the histone acetylase p300 to the insulin gene promoter. A detailed understanding of the molecular mechanisms by which high blood glucose levels regulate beta-cell specific gene expression in the pancreas, will contribute to the design of specific strategies such as the production of insulin from non-beta cells to .treat and prevent the major complications associated with diabetes. The information obtained will also help in the development of new clinical interventions to reduce or eliminate the secondary complications, suct)as cardiovascular disease associated with chronic hyperglycemia.