Distribution of Methylated Regions Within gDNA in Acute and Chronic Phases of Diabetes Mellitus

Abstract

Diabetes mellitus (DM) is a disease of metabolic dysregulation involving the induction of hyperglycemia due to (1) loss of functioning of pancreatic beta cells that produce insulin (t1 DM) or (2) the inability of systemic cells to properly respond to the insulin signal (t2 DM). The resulting hyperglycemic episodes induce long-term complications in a broad spectrum of organs/tissues such as seen in the cardiovascular system (CV). One aspect of CV dysregulation is seen in abnormalities in blood vessel formation (BVF). These abnormalities in BVF are seen in the acute and chronic states of DM, with the latter chronic effects termed “metabolic memory” (MM). The heritable nature of metabolic memory indicates a role for the epigenome as a contributing factor in DM and MM. In this regard, the epigenome is comprised of all chromatin-modifying processes such as DNA methylation and histone modifications that allow cells and organisms to quickly respond to changing environmental stimuli. The current review focuses on the global patterns of gDNA methylation in Control, DM, and MM groups using a zebrafish DM/MM model of the disease. For this review, global analysis is focused on 10 Kb upstream from the TSS (transcription start site), 1 Kb upstream from the TSS, and 300 bp downstream of the TSS for all genes of the zebrafish genome. Analysis of gDNA methylation patterns will also be studied in regard to genes that regulate BVF, and we have included genes that control DNA replication and repair in this regulatory group. As will be discussed, hyperglycemia not only induces changes in gDNA methylation but complex changes in the pattern seen in the methylation and demethylation of BVF regulatory genes.