DNA methylation profiling in cell models of diabetic nephropathy

Brennan, Eoin; Ehrich, Mathias; O'Donovan, Helen; Brazil, Derek P.; Crean, John; Murphy, Madeline; Sadlier, Denise; Martin, Finian; Godson, Catherine; Boom, Dirk van den; Maxwell, Alexander P.; Savage, David A.

doi:10.4161/epi.5.5.12077

Cited by 27 publications

(18 citation statements)

References 32 publications

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“…Recently, several studies suggested the involvement of DNA methylation changes in kidney diseases, including kidney fibrosis, 26-28 diabetic nephropathy, 29, 30 and chronic kidney disease. 31, 32 However, very limited is known about the role and regulation of DNA methylation in AKI.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

Guo

Pei

Xiao

et al. 2017

Kidney International

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DNA methylation is an epigenetic mechanism that regulates gene transcription without changing primary nucleotide sequences. In mammals, DNA methylation involves the covalent addition of a methyl group to the 5-carbon position of cytosine by DNA methyltransferases (DNMTs). The change of DNA methylation and its pathological role in acute kidney injury (AKI) remain largely unknown. Here, we analyzed genome-wide DNA methylation during cisplatin-induced AKI by reduced representation bisulfite sequencing. This technique identified 215 differentially methylated regions between the kidneys of control and cisplatin-treated animals. While most of the differentially methylated regions were in the intergenic, intronic and coding DNA sequences, some were located in the promoter or promoter regulatory regions of 15 protein-coding genes. To determine the pathological role of DNA methylation, we initially examined the effects of DNA methylation inhibitor 5-Aza-2′-deoxycytidine and showed it increased cisplatin-induced apoptosis in a rat kidney proximal tubular cell line. We further established a kidney proximal tubule-specific DNMT1 (PT-DNMT1) knockout mouse model, which showed more severe AKI during cisplatin treatment than wild-type mice. Finally, interferon regulatory factor 8 (Irf8), a pro-apoptotic factor, was identified as a hypomethylated gene in cisplatin-induced AKI and this hypomethylation was associated with a marked induction of Irf8. In the rat kidney proximal tubular cells, knockdown of Irf8 suppressed cisplatin-induced apoptosis, supporting a pro-death role of Irf8 in renal tubular cells. Thus, DNA methylation plays a protective role in cisplatin-induced AKI by regulating specific genes, such as Irf8.

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Section: Introductionmentioning

confidence: 99%

DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

Guo

Pei

Xiao

et al. 2017

Kidney International

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“…Although aberrant DNA-me has been reported to be associated with cancer progression (13,16,38), only a few studies have examined the role of DNA-me in T1D complications (23,(32)(33)(34)39). Notably, it is unknown if DNA-me persists over time in people with diabetes and is associated with metabolic memory.…”

mentioning

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.

197

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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“…Very little literature exists on polymorphisms in SCUBE3 but this gene appears to be associated with hypermethylation in some cancers [17,18]. SCUBE3 is also involved in angiogenesis and is strongly expressed in aggressive lung carcinomas [45,46].…”

Section: Discussionmentioning

confidence: 99%

“…Additional genes, namely SCUBE3, PPP6R3 and PHF-11 , were selected based on an analysis of the VDR pathway (unpublished data). SCUBE3 appears to be associated with hypermethylation in some cancers [17,18], and is associated with the VDR pathway. The main functions of PPP6R3 include transcription, translation, morphogenesis and cell-cycle regulation [19] and PPP6R3 is also believed to be active in the VDR pathway.…”

Section: Introductionmentioning

confidence: 99%

The Role of Vitamin D Level and Related Single Nucleotide Polymorphisms in Crohn’s Disease

et al. 2013

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New Zealand has one of the highest rates of Crohn’s Disease (CD) in the world, and there is much speculation as to why this might be. A high risk of CD has been associated with deficient or insufficient levels of Vitamin D (Vit D), lifestyle as well as various genetic polymorphisms. In this study we sought to analyse the relevance of serum Vit D levels, lifestyle and genotype to CD status. Serum samples were analysed for 25-OH-Vitamin D levels. DNA was isolated from blood and cheek-swabs, and Sequenom and ImmunoChip techniques were used for genotyping. Serum Vit D levels were significantly lower in CD patients (mean = 49.5 mg/L) than those found in controls (mean = 58.9 mg/L, p = 4.74 × 10−6). A total of seven single nucleotide polymorphisms were examined for effects on serum Vit D levels, with adjustment for confounding variables. Two variants: rs731236[A] (VDR) and rs732594[A] (SCUBE3) showed a significant association with serum Vit D levels in CD patients. Four variants: rs7975232[A] (VDR), rs732594[A] (SCUBE3), and rs2980[T] and rs2981[A] (PHF-11) showed a significant association with serum Vit D levels in the control group. This study demonstrates a significant interaction between Vit D levels and CD susceptibility, as well as a significant association between Vit D levels and genotype.

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DNA methylation profiling in cell models of diabetic nephropathy

Cited by 27 publications

References 32 publications

DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

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

The Role of Vitamin D Level and Related Single Nucleotide Polymorphisms in Crohn’s Disease

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