Role of HIstone Modification in Glucose Regulation of Insulin Gene Expression

A tight regulation of insulin production and release by the pancreatic beta cells is essential in maintaining glucose homeostasis. Defects in insulin secretion and biosynthesis result in high blood glucose levels (hyperglycemia). Chronic hyperglycemia is responsible for most of the secondary complications associated with type II diabetes, including cardiovascular disease, kidney failure, blindness, and amputations. Although, several transcription factors have been implicated in glucose regulation of insulin gene expression, including Pdx-l, Beta- 2 and Ribe3b l, the exact molecular events leading to up-regulation of insulin gene transcription in response to high blood glucose levels are unknown. We have recently discovered that glucose regulation of insulin gene expression is mediated by changes in histone acetylationvia Pdx-l. . These data suggest that glucose stimulation of insulin gene transcription is mediated by hyperacetylation of histones at the insulin gene promoter. To test this hypothesis we propose the following specific aims: 1. Determining the role of the transcription factor Pdx-l in the recruitment of the histone acetylase p300 to the insulin gene promoter. ' 2. Analysis of the role of the deacetylase Hdacl and the O-linked GlcNAc transferase OGTl in repression of insulin gene transcription.