Glycemic memory associated epigenetic changes
Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia. Biochemical pharmacology
(Impact Factor: 5.01).
12/2010; 80(12):1853-9. DOI: 10.1016/j.bcp.2010.06.005
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.
Available from: Charlie C Xue
- "Recent studies indicate that acetylation of key transcription factors can maintain an induced phenotype even the trigger is no longer present , . Protein acetylation is regulated by histone acetyltransferases (HATs) and deacetylases (HDACs) . "
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ABSTRACT: Our recent study (referred as Study 1) showed that the triterpenoid oleanolic acid (OA) was able to produce a sustained correction of hyperglycemia beyond treatment period in type 2 diabetes (T2D) mice with liver as a responsible site. To follow up the previous observations, the present study (referred as Study 2) investigated the possible role of acetylation of FoxO1 and associated events in this therapeutic memory by characterizing the pathways regulating the acetylation status during and post-OA treatments. OA treatment (100 mg/kg/day for 4 weeks, during OA treatment) reduced hyperglycemia in T2D mice by ∼87% and this effect was largely (∼70%) maintained even 4 weeks after the cessation of OA administration (post-OA treatment). During OA treatment, the acetylation and phosphorylation of FoxO1 were markedly increased (1.5 to 2.5-fold) while G6Pase expression was suppressed by ∼80%. Consistent with this, OA treatment reversed pyruvate intolerance in high-fat fed mice. Histone acetyltransferase 1 (HAT1) content was increased (>50%) and histone deacetylases (HDACs) 4 and 5 (not HDAC1) were reduced by 30-50%. The OA-induced changes in FoxO1, G6Pase, HAT1 and HDACs persisted during the post-OA treatment period when the increased phosphorylation of AMPK, SIRT1 content and reduced liver triglyceride had subsided. These results confirmed the ability of OA to control hyperglycemia far beyond treatment period in T2D mice. Most importantly, in the present study we demonstrated acetylation of FoxO1 in the liver is involved in OA-induced memory for the control of hyperglycemia. Our novel findings suggest that acetylation of the key regulatory proteins of hepatic gluconeogenesis is a plausible mechanism by the triterpenoid to achieve a sustained glycemic control for T2D.
PLoS ONE 09/2014; 9(9):e107231. DOI:10.1371/journal.pone.0107231 · 3.23 Impact Factor
Available from: Rosa Puca
- "Moreover, hyperglycemia has been demonstrated to alter gene expression and even to drive the mesodermal transdifferentiation of MSCs towards a preferential adipogenic pathway at the expense of the chondrogenic and osteogenic lineages  . In other cell systems such as endothelial cells, transient hyperglycemia has been reported to cause relevant transcriptional changes, thus offering an explanation for the persistent presence of systemic complications in diabetic patients returning to normal glycemic levels . Taken together these observations have suggested that damage caused by a dysregulation in the glucose level tolerance may affect stem cell properties in a long term and irreversible fashion. "
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ABSTRACT: Mesenchymal stem cells (MSCs) represent a promising cell population for cell therapy and regenerative medicine applications. However, how variations in glucose are perceived by MSC pool is still unclear. Since, glucose metabolism is cell type and tissue dependent, this must be considered when MSCs are derived from alternative sources such as the heart. The zinc finger transcription factor Egr-1 is an important early response gene, likely to play a key role in the glucose-induced response. Our aim was to investigate how short-term changes in in vitro glucose concentrations affect multipotent cardiac tissue-derived MSCs (cMSCs) in a mouse model of Egr-1 KO (Egr-1(-/-)). Results showed that loss of Egr-1 does not significantly influence cMSC proliferation. In contrast, responses to glucose variations were observed in wt but not in Egr-1(-/-) cMSCs by clonogenic assay. Phenotype analysis by RT-PCR showed that cMSCs Egr-1(-/-) lost the ability to regulate the glucose transporters GLUT-1 and GLUT-4 and, as expected, the Egr-1 target genes VEGF, TGF β -1, and p300. Acetylated protein levels of H3 histone were impaired in Egr-1(-/-) compared to wt cMSCs. We propose that Egr-1 acts as immediate glucose biological sensor in cMSCs after a short period of stimuli, likely inducing epigenetic modifications.
BioMed Research International 05/2014; 2014(10):11. DOI:10.1155/2014/254793 · 1.58 Impact Factor
Available from: Zhila Maghbooli
- "There is growing evidence that gene-gene interactions and gene-environmental interactions play an important role in determining an individual’s risk of various common diseases including diabetes . Recent evidence shows that most gene expressions and gene-environmental interactions are mediated by epigenetic modulations [31-33]. Epigenetic mechanisms provide a framework to incorporate environmental factors into models of complex disorder risks. "
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The aim of this study was assessment of predictive factors of diabetic retinopathy.
A cross-sectional study was designed by recruiting 1228 type 2 diabetic patients from a diabetes referral clinic over a six-month period (from July to December, 2012). Diabetes risk factors, complications, laboratory results have been recorded.
Of the 1228 diabetic patients (54% women, mean age 58.48 ± 9.94 years), prevalence of diabetes retinopathy was 26.6%. There were significant associations between retinopathy and family history of diabetes (p = 0.04), hypertension (p = 0.0001), diabetic duration (p = 0.0001), poor glycemic control (p = 0.0001) and age of onset of diabetes (p = 0.0001). However, no significant associations were found between retinopathy with dyslipidemia and obesity. In logistic regression model, poor glycemic control (p = 0.014), hypertension (p = 0.0001), duration of diabetes (p = 0.0001) and family history of diabetes (p = 0.012) independently predicted retinopathy after adjustment for age and sex.
Diabetic complications are resulting from an interaction from genes and environmental factors. A family history of diabetes is pointing toward a possible genetic and epigenetic basis for diabetic retinopathy. Our findings suggest the role of epigenetic modifications and metabolic memory in diabetic retinopathy in subjects with family history of diabetes.
Journal of Diabetes and Metabolic Disorders 05/2014; 13(1):55. DOI:10.1186/2251-6581-13-55
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