title: Glycemic memory associated epigenetic changes.
abstract: It is evident that metabolic memory, whereby diabetic complications continue to develop and progress in individuals who returned to normal glycemic control after a period of transient hyperglycemia, can have long lasting effects. We have primary findings that transient hyperglycemia causes profound transcriptional changes in vascular endothelial cells. We hypothesized that ambient hyperglycemia triggers gene-activating events of the NFκB p65 promoter that are mediated by changes in epigenetic modifications. In a follow-up study we identified two histone-specific writing and erasing enzymes involved in the underlying regulation of gene expression during transient hyperglycemia and subsequent return to normoglycemia. Experimental evidence indicates that previous hyperglycemia is associated with persistent expression of the NFκB p65 gene, which activates NFκB-dependent proteins, such as MCP-1, which are implicated in diabetes-associated vascular injury. Increased gene transcription is correspondent with H3K4m1, but not H3K4m2 and H3K4m3, on the NFκB p65 gene. In vascular endothelial cells the histone methyltransferase Set7 can write the mono-methylation mark H3K4m1 and this methyl-writing enzyme is recruited as a gene co-activator in response to glucose. Furthermore, Set7 knockdown prevents glucose-induced p65 expression. We hypothesize that these molecular events represent an integrated response of the epigenome that lead to changes in the expression of genes and proteins that regulate the development and progression of diabetic vascular complications. Further characterisation of these glucose-induced epigenetic events and the identification of key enzymes involved will improve our understanding of the pathways implicated in diabetic vascular injury.
authors.affiliation: Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Siebel
authors.forename: Ana Z
authors.initials: AZ
authors.lastname: Fernandez
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000209:etiology / Q000378:metabolism; D048909:Diabetes Complications / Q000235:genetics / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism*; D009747:Nutritional Physiological Phenomena
chemical_list: D006657:Histones