Cytosine methylation changes in enhancer regions of core pro-fibrotic genes characterize kidney fibrosis development

Ko, Yi-An; Mohtat, Davoud; Suzuki, Masako; Park, Ae Seo Deok; Izquierdo, María C.; Han, Sang Youb; Kang, Hyun Mi; Si, Han; Hostetter, Thomas H.; Pullman, James; Fazzari, Melissa; Verma, Amit; Zheng, Deyou; Greally, John M.; Suszták, Katalin

doi:10.1186/gb-2013-14-10-r108

Cited by 201 publications

(223 citation statements)

References 34 publications

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“…Major changes in DNA-me distribution at promoters are a hallmark of cancer (13,16). However, in chronic diseases, such as diabetes and its complications, increasing evidence suggests the importance of DNA-me in regulatory regions, including putative enhancer regions in kidney tissues from patients with diabetic kidney disease (50), intronic enhancers in blood cells type 2 diabetes patients (51), and gene bodies/intergenic regions rather than promoters in adipose tissues from twins (52). The high percentage of DMLs in intergenic regions, introns, and 3′ UTRs in our study is in line with such reports.…”

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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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: 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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“…We acquired the histone marks from human kidney proximal tubule cells that we previously published, 39 as well as from human kidney tissues at the Roadmap Epigenome Project (GEO: GSM621634, GSM670025, GSM621648, GSM772811, GSM621651, GSM1112806, GSM621638). Human kidney cell (HKC8) ChIP-seq data can be accessed at Gene Expression Omnibus (GEO: GSE49637), and Transcription Factor ChIP-seq (161 factors) from ENCODE project TFBS clusters (V3).…”

Section: Histone Mark and Transcription Factor Binding Site Enrichmenmentioning

confidence: 99%

“…We performed this analysis using different histone tail mark-specific antibodies and human kidney-proximal tubule cells (HKC8) 39 because proximal tubule make up most ($90%) cells in the renal cortex. We overlapped kidney eQTL SNPs with each histone mark, quantifying the enrichment ratio by comparing it with 1,000 randomly generated SNP sets that were matched for frequency and distance.…”

Section: Validation and Replication Of Kidney Cis-eqtl Signalsmentioning

confidence: 99%

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

Qiu

et al. 2017

The American Journal of Human Genetics

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Chronic kidney disease (CKD) is a complex gene-environmental disease affecting close to 10% of the US population. Genome-wide association studies (GWASs) have identified sequence variants, localized to non-coding genomic regions, associated with kidney function. Despite these robust observations, the mechanism by which variants lead to CKD remains a critical unanswered question. Expression quantitative trait loci (eQTL) analysis is a method to identify genetic variation associated with gene expression changes in specific tissue types. We hypothesized that an integrative analysis combining CKD GWAS and kidney eQTL results can identify candidate genes for CKD. We performed eQTL analysis by correlating genotype with RNA-seq-based gene expression levels in 96 human kidney samples. Applying stringent statistical criteria, we detected 1,886 genes whose expression differs with the sequence variants. Using direct overlap and Bayesian methods, we identified new potential target genes for CKD. With respect to one of the target genes, lysosomal beta A mannosidase (MANBA), we observed that genetic variants associated with MANBA expression in the kidney showed statistically significant colocalization with variants identified in CKD GWASs, indicating that MANBA is a potential target gene for CKD. The expression of MANBA was significantly lower in kidneys of subjects with risk alleles. Suppressing manba expression in zebrafish resulted in renal tubule defects and pericardial edema, phenotypes typically induced by kidney dysfunction. Our analysis shows that gene-expression changes driven by genetic variation in the kidney can highlight potential new target genes for CKD development.

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“…Angiotensin receptor blockers may also in part work through correction of epigenetic changes (332). Compared to healthy samples, in tubular cells of patients with CKD and fibrosis, a genome-wide methylation approach showed significant epigenetic regulation of the main pro-fibrotic genes (333). First data on epigenetics in allograft fibrosis are emerging (334) but overall little is known about this situation so far.…”

Section: Epigeneticsmentioning

confidence: 99%

Renal Allograft Fibrosis: Biology and Therapeutic Targets

Floege

2015

American Journal of Transplantation

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Cytosine methylation changes in enhancer regions of core pro-fibrotic genes characterize kidney fibrosis development

Cited by 201 publications

References 34 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

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

Renal Allograft Fibrosis: Biology and Therapeutic Targets

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