DNA hypermethylation and DNA hypomethylation is present at different loci in chronic kidney disease

Smyth, Laura; McKay, Gareth J.; Maxwell, Alexander P.; McKnight, Amy Jayne

doi:10.4161/epi.27161

Cited by 137 publications

(179 citation statements)

References 74 publications

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“…However, the functions of DNA-me at these regions and how they might contribute to gene expression are not yet clear. Only ∼10% of DMLs were located in CGI, whereas the majority were in open seas in both WB and Monos, consistent with findings in WB from monozygotic twins (54), β-cells of type 2 diabetes (55), and WB of chronic kidney disease patients (56). This result is in the contrast to high enrichment in CGIs and their shores in cancer (13,16).…”

Section: Discussioncontrasting

confidence: 51%

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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.

200

185

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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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Section: Discussioncontrasting

confidence: 51%

“…However, quite often, obtaining such tissues requires invasive approaches, and there is a paucity of such tissues. Because most diabetic complications are associated with inflammation, WBCs, including inflammatory Monos, which exhibit similar DNA-me changes as those in specific tissues, are good and easily accessible "surrogates" (56).…”

Section: Discussionmentioning

confidence: 99%

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.

200

185

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“…Ultimately, allograft quality will be related to organ resilience to stress, and this by itself provides an opportunity for the development of new therapeutic interventions aimed at exploiting this phenomenon. Recent studies focusing on the progression of chronic kidney disease (CKD) have exemplified the importance of epigenetic changes and loss of kidney function (Smyth, McKay, Maxwell, & McKnight, 2014; Wing et al, 2014). Our data have indicated rapid changes in the epigenome during perfusion, suggesting that the effect of IRI on long‐term allograft function may be more pronounced than originally anticipated.…”

Section: Discussionmentioning

confidence: 99%

A molecular signature for delayed graft function

et al. 2018

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Chronic kidney disease and associated comorbidities (diabetes, cardiovascular diseases) manifest with an accelerated ageing phenotype, leading ultimately to organ failure and renal replacement therapy. This process can be modulated by epigenetic and environmental factors which promote loss of physiological function and resilience to stress earlier, linking biological age with adverse outcomes post‐transplantation including delayed graft function (DGF). The molecular features underpinning this have yet to be fully elucidated. We have determined a molecular signature for loss of resilience and impaired physiological function, via a synchronous genome, transcriptome and proteome snapshot, using human renal allografts as a source of healthy tissue as an in vivo model of ageing in humans. This comprises 42 specific transcripts, related through IFNγ signalling, which in allografts displaying clinically impaired physiological function (DGF) exhibited a greater magnitude of change in transcriptional amplitude and elevated expression of noncoding RNAs and pseudogenes, consistent with increased allostatic load. This was accompanied by increased DNA methylation within the promoter and intragenic regions of the DGF panel in preperfusion allografts with immediate graft function. Pathway analysis indicated that an inability to sufficiently resolve inflammatory responses was enabled by decreased resilience to stress and resulted in impaired physiological function in biologically older allografts. Cross‐comparison with publically available data sets for renal pathologies identified significant transcriptional commonality for over 20 DGF transcripts. Our data are clinically relevant and important, as they provide a clear molecular signature for the burden of “wear and tear” within the kidney and thus age‐related physiological capability and resilience.

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“…14) Recent studies reported that epigenetics, such as DNA methylation and histone modifications, play pivotal roles in the progression of CKD, and some inhibitors of histone deacetylase (HDAC) exert beneficial effects against CKD. [15][16][17] Moreover, the expression of EC-SOD is known to be regulated by epigenetics in human lung cancer cells, 18,19) monocytes/macrophages, 20) and retina endothelial cells 21) ; however, limited information is currently available on EC-SOD regulation mechanisms in CKD models and the involvement of epigenetics.…”

mentioning

confidence: 99%

CoCl<sub>2</sub> Decreases EC-SOD Expression through Histone Deacetylation in COS7 Cells

Hattori

Kamiya

Hara

et al. 2016

Biological & Pharmaceutical Bulletin

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Extracellular-superoxide dismutase (EC-SOD), one of the SOD isozymes, is negatively regulated under hypoxic conditions, and decreases in its expression may exacerbate vascular diseases. Moreover, epigenetics, such as DNA methylation and histone modifications, are known to play a critical role in the progression of cancer, type 2 diabetes, and atherosclerosis. We previously investigated the involvement of reactive oxygen species (ROS) and p38 mitogen-activated protein kinase (MAPK) in decreases in EC-SOD expression in hypoxic COS7 cells; however, the role of epigenetics in this process currently remains unknown. In the present study, we demonstrated that the hypoxia mimetic cobalt chloride (CoCl 2 ) decreased histone acetylation levels, and a pretreatment with 4-phenyl butyric acid (PBA), an inhibitor of histone deacetylase, significantly suppressed CoCl 2 -elicited histone deacetylation and decreases in EC-SOD. We found that CoCl 2 -elicited decreases in EC-SOD were accompanied by reductions in histone H3 acetylation levels within its promoter region. Furthermore, luteolin, a well-known flavonoid, significantly suppressed the CoCl 2 -elicited accumulation of ROS, p38-MAPK activation, and histone deacetylation. Collectively, the results of the present study showed for the first time that CoCl 2 decreases the expression of EC-SOD through its deacetylation and luteolin may be one of the seed compounds that maintain redox homeostasis, even under hypoxic conditions.

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DNA hypermethylation and DNA hypomethylation is present at different loci in chronic kidney disease

Cited by 137 publications

References 74 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

A molecular signature for delayed graft function

CoCl<sub>2</sub> Decreases EC-SOD Expression through Histone Deacetylation in COS7 Cells

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