Evaluating the Role of Epigenetic Histone Modifications in the Metabolic Memory of Type 1 Diabetes

Miao, Feng; Chen, Zhuo; Genuth, Saul; Paterson, Andrew D.; Zhang, Lingxiao; Wu, Xiwei; Li, Sierra Min; Cleary, Patricia A.; Riggs, Arthur D.; Harlan, David M.; Lorenzi, Gayle M.; Kolterman, Orville G.; Sun, Wanjie; Lachin, John M.; Natarajan, Rama

doi:10.2337/db13-1251

Cited by 215 publications

(157 citation statements)

References 51 publications

(51 reference statements)

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“…Notably, it is unknown if DNA-me persists over time in people with diabetes and is associated with metabolic memory. Here, we addressed this issue by using DNA collected at two different time points (EDIC Study baseline and EDIC Study years 16 and 17) from the same DCCT/EDIC Study cohort in which we previously evaluated histone PTMs (31). To our knowledge, this study is the first one in which two sets of DNAs collected at least 16-17 y apart from the same participants are used to show the persistency of DNA-me over time.…”

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confidence: 99%

“…Several laboratories, including our laboratory, using cell and animal models have suggested roles for key histone PTMs in high glucose (HG)-mediated effects, diabetic complications, and metabolic memory (9,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Histone PTM profiling of vascular and inflammatory cells cultured with HG vs. normal glucose (NG) or WBCs from T1D patients vs. healthy volunteers or T1D patients with complications vs. those without depicted significant PTM differences and candidate differentially methylated or acetylated genes relevant to diabetes or its complications (23,(32)(33)(34).…”

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confidence: 99%

“…We recently did histone PTMs profiling (31) in peripheral blood monocytes (Monos) and lymphocytes collected from 30 former DCCT CONV group subjects (cases; mean DCCT HbA1c > 9.1% and progression of retinopathy or macroalbuminuria by EDIC Study year 10 of follow-up) vs. 30 former DCCT INT subjects (controls; mean DCCT HbA1c < 7.3% and without progression through EDIC Study year 10). We showed that Monos from cases were significantly enriched with histone H3-lysine9-acetylation (H3K9Ac) relative to controls at promoter regions.…”

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Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort

Chen

Miao

Paterson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We examined whether persistence of epigenetic DNA methylation (DNA-me) alterations at specific loci over two different time points in people with diabetes are associated with metabolic memory, the prolonged beneficial effects of intensive vs. conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term followup Epidemiology of Diabetes Interventions and Complications (EDIC) Study. We compared DNA-me profiles in genomic DNA of whole blood (WB) isolated at EDIC Study baseline from 32 cases (DCCT conventional therapy group subjects showing retinopathy or albuminuria progression by EDIC Study year 10) vs. 31 controls (DCCT intensive therapy group subjects without complication progression by EDIC year 10). DNA-me was also profiled in blood monocytes (Monos) of the same patients obtained during EDIC Study years 16-17. In WB, 153 loci depicted hypomethylation, and 225 depicted hypermethylation, whereas in Monos, 155 hypomethylated loci and 247 hypermethylated loci were found (fold change ≥1.3; P < 0.005; cases vs. controls). Twelve annotated differentially methylated loci were common in both WB and Monos, including thioredoxin-interacting protein (TXNIP), known to be associated with hyperglycemia and related complications. A set of differentially methylated loci depicted similar trends of associations with prior HbA1c in both WB and Monos. In vitro, high glucose induced similar persistent hypomethylation at TXNIP in cultured THP1 Monos. These results show that DNA-me differences during the DCCT persist at certain loci associated with glycemia for several years during the EDIC Study and support an epigenetic explanation for metabolic memory.T he landmark Diabetes Control and Complications Trial (DCCT; 1983-1993 clearly showed that intensive (INT) glycemic control profoundly reduces the development and progression of microvascular complications in type 1 diabetes (T1D). The DCCT participants were subsequently followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) Study (1994 to present), during which all subjects were advised to practice INT treatment. Surprisingly, those previously assigned to conventional (CONV) therapy continued to develop complications, such as nephropathy, retinopathy, and macrovascular diseases, at significantly higher rates than the previous INT therapy group, despite nearly similar HbA1c levels during the EDIC Study (1-3). This persistence of benefit from early application of INT therapy, called "metabolic memory," is an enigma in the field of T1D: recent studies have suggested the involvement of epigenetic mechanisms (4-9).Epigenetics is the study of mostly heritable changes in gene expression and phenotype that occur without alterations in the underlying DNA sequence. Epigenetic states are affected by environmental factors, such as aberrant nutrition and metabolic states (4, 6-8, 10). DNA methylation (DNA-me; the classic epigenetic mark) and posttranslational modifications (PTMs) of histo...

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Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort

Chen

Miao

Paterson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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196

185

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“…The Chez ces patients, les complications du diabète causées par l'hyperglycémie transitoire persistent voire progressent, alors même que la glycémie est contrôlée par l'administration d'insuline [51]. L'analyse des modifications post-traductionnelles des histones dans des cellules sanguines de patients atteints de diabète de type 1 (DT1) a montré que l'acétylation de la lysine 9 de l'histone H3 (H3K9ac) est modifiée [52]. De façon similaire, in vitro dans des cellules endothéliales primaires exposées à une hyperglycémie, cette acétylation de l'histone H3 est diminuée sur un nombre significatif de régions promotrices de gènes impliqués dans la physiopathologie du DT1 [53].…”

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Le nouveau paradigme de l’origine développementale de la santé et des maladies (DOHaD)

et al. 2016

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“…In vascular smooth muscle cells derived from type 2 diabetic mice, irreversibly decreased levels of both H3K9me3 and methyltransferase Suv39H1 at the promoters of interleukin-6 and monocyte chemoattractant protein1 are observed, and SUV39H1 gene silencing irreversibly elevates the expression of inflammatory genes and decreases H3K9me3 at their promoters [57]. Monocytes from case subjects enrolled in landmark the Diabetes Control and Complications Trial and the follow up Epidemiology of Diabetes Interventions and Complications study have shown a significant association between H3K9 acetylation and hemoglobin A1C levels [58].…”

Section: Epigenetic Modification and Diabetesmentioning

confidence: 99%

Contribution of epigenetics in diabetic retinopathy

Kowluru

Mishra

2015

Sci. China Life Sci.

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Diabetes has become the epidemic of the 21st century, and with over 90% patients with diabetes becoming at a risk of developing retinopathy, diabetic retinopathy has emerged as a major public health concern. In spite of cutting edge research in the field, how retina and its vasculature are damaged by the diabetic milieu remains ambiguous. The environmental factors, life style or disease process can also bring in modifications in the DNA, and these epigenetic modifications either silence or activate a gene without altering the DNA sequence. Diabetic environment up-or downregulates a number of genes in the retina, and emerging research has shown that it also facilitates epigenetic modifications. In the pathogenesis of diabetic retinopathy, the genes associated with important enzymes (e.g., mitochondrial superoxide dismutase, matrix metalloproteinase-9 and thioredoxin interacting protein) and transcriptional factors are epigenetically modified, the enzymes responsible for these epigenetic modifications are either activated or inhibited, and the levels of microRNAs are altered. With epigenetic modifications taking an important place in diabetic retinopathy, it is now becoming critical to evaluate these modifications, and understand their impact on this slow progressing blinding disease. diabetic retinopathy, epigenetic modifications, histone acetylation, histone methylation, miRNA Citation:Kowluru RA, Mishra M. Contribution of epigenetics in diabetic retinopathy.

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Evaluating the Role of Epigenetic Histone Modifications in the Metabolic Memory of Type 1 Diabetes

Cited by 215 publications

References 51 publications

Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort

Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort

Le nouveau paradigme de l’origine développementale de la santé et des maladies (DOHaD)

Contribution of epigenetics in diabetic retinopathy

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