Epigenetic Mechanisms of Metabolic Memory in Diabetes Mellitus
Diabetes mellitus affects 24 million Americans, while an additional 57 million more are considered to be at risk for the development of this disease. Epidemiological studies suggest that patients with diabetes have a 2-10 fold increased risk of cardiovascular disease as compared to their non-diabetic counterparts. Two recent landmark clinical trials both demonstrated that early aggressive treatment of hyperglycemia to achieve “tight control” of blood glucose in patients with Type 1 and Type 2 diabetes mellitus protected against the future development of cardiovascular disease, even if glycemic control had subsequently lapsed. These observations have led to the idea that a “metabolic memory” for blood glucose control exists in patients with diabetes and predicts the development of later disease sequelae. At present, the molecular mechanisms underlying the concept of metabolic memory are unknown. The long-range goal of this applicant is to fill this knowledge gap and define the role of epigenetics in the development of metabolic memory and diabetic cardiovascular disease. The hypothesis underlying this proposal is that Set7/9 is a chromatin modifying cofactor that plays a permissive role in the development of atherosclerosis in diabetes mellitus, through its interaction with and subsequent histone methylation of a subset of pro-inflammatory NF-?B target genes in the macrophage. It is further predicted that these Set7/9-mediated chromatin effects persist even after resolution of hyperglycemia, thus providing a mechanistic basis for the clinical observation of metabolic memory. In order to test this hypothesis, a model of macrophage specific deletion of Set7/9 (mSet7/9KO) has been generated. Using this novel reagent, two specific aims are proposed for this application. The first is to generate and validate the mSet7/9KO mouse and to expose this model to sustained and intermittent hyperglycemia. The second aim is to characterize the molecular and epigenetic effects of Set7/9 deletion in the macrophage in the context of sustained and intermittent exposure to a diabetic metabolic milieu. As part of this aim, macrophages from our mSet7/9KO model will be used for transcriptional analysis, macrophage functional assays, and chromatin immunoprecipitation experiments.

Curation Flag Information