Comprehensive characterization of DNA methylation changes in Fuchs endothelial corneal dystrophy

Khuc, Emily; Bainer, Russell; Wolf, Marie; Clay, Selene M.; Weisenberger, Daniel J.; Kemmer, Jacquelyn D.; Weaver, Valerie M.; Hwang, David G.; Chan, Matilda F.

doi:10.1371/journal.pone.0175112

Cited by 28 publications

(47 citation statements)

References 70 publications

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“…Together, these data show that the majority of differentially methylated miRNA probes occur in intragenic and intronic sequences of their host genes. Our prior genome-scale analysis of the DNA methylation landscape of corneal endothelial tissue found a significant difference between FECD and normal control patients [30].…”

Section: Resultsmentioning

confidence: 99%

“…To validate and quantify miRNA DNA hypermethylation changes identified by the global array [30], MethyLight analysis was performed on an additional cohort of control and FECD patient corneal samples (Table 3) [42]. MethyLight assessed the promoter DNA methylation status of following miRNAs: miR-199A1, miR-874, miR-140, miR-23B, and miR-1306 ( Fig S1, Table S1 ).…”

Section: Resultsmentioning

confidence: 99%

“…FECD is the most common type of corneal endothelial dystrophy and a leading indication for corneal transplantation in patients in the United States [6, 57]. We previously identified global DNA methylation changes that occur in the corneal endothelial tissue of FECD patients and specifically observed a high number of DNA methylation alterations occurring in miRNA sequences [30]. This finding was intriguing because prior reports had demonstrated that miRNAs were differentially expressed in the corneal endothelium during aging [58], and that widespread downregulation of miRNA levels occurred in the corneal endothelium of patients with late-onset FECD [36, 59].…”

Section: Discussionmentioning

confidence: 99%

“…Statistical analyses on genome-wide methylation data of miRNA genes were executed in R [30]. All other analyses were performed using two-tailed t-tests to compare mean values using R software.…”

Section: Methodsmentioning

confidence: 99%

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Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

Pan

Weisenberger

Zheng

et al. 2019

Preprint

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18Homeostatic maintenance of corneal endothelial cells is essential for maintenance of corneal 19 deturgescence and corneal transparency. In Fuchs endothelial corneal dystrophy (FECD), an 20 accelerated loss and dysfunction of endothelial cells leads to progressively severe visual 21impairment. An abnormal accumulation of extracellular matrix is a distinctive hallmark of the 22 disease, however the molecular pathogenic mechanisms underlying this phenomenon are not fully 23 understood. We recently reported characteristic patterns of DNA methylation changes in the 24 corneal endothelial cells of patients with FECD. Here, we investigate genome-wide and sequence-25 specific DNA methylation changes of miRNA genes in corneal endothelial samples derived from 26 patients with FECD. We show that the majority of miRNA genes are hypermethylated at their 27 promoter regions in FECD. More specifically, miR-199B is an extensively hypermethylated 28 miRNA gene at its promoter region and its mature transcript miR-199b-5p was previously found 29 to be almost completely silenced in FECD. Using a cell-based assay, we find that miR-199b-5p 30 directly inhibits the expression of two epithelial mesenchymal transition (EMT)-inducing genes, 31Snai1 and ZEB1. Taken together, these findings suggest a novel regulatory mechanism of matrix 32 protein production by corneal endothelial cells in which miR-199b-5p hypermethylation leads to 33 its down-regulated expression and thereby the decreased expression of miR-199b-5p target genes, 34including Snai1 and ZEB1. Our results support miR-199b-5p as a potential therapeutic target to 35 prevent or slow down the progression of FECD disease. 36 37 Author summary 38 Fuchs endothelial corneal dystrophy (FECD) due to corneal endothelial cell degeneration is one 39 of the most common heritable causes of corneal visual loss and a leading indication for corneal 40 3 transplantation. The progressive loss of corneal endothelial cells is accompanied by an abnormal 41 deposition of extracellular matrix in the form of guttae. Here we discover that miRNA gene 42 promoters are frequent targets of aberrant DNA methylation in FECD. In particular, we describe 43 a novel epigenetic mechanism used by corneal endothelial cells to regulate extracellular matrix 44 production. We find that miRNA-199b-5p functions as a negative regulator of Snai1 and ZEB1, 45 two zinc finger transcription factors that have been shown to lead to increased production of 46 extracellular matrix proteins. Furthermore, miR-199B was extensively hypermethylated in FECD 47 and its mature transcript miR-199b-5p directly binds to the 3′-UTRs of Snai1 and ZEB1 genes. 48Ultimately, this may negatively modulate Snai1-and ZEB1-mediated production of extracellular 49 matrix proteins. This work is the first to identify an important role of DNA methylation in the 50 epigenetic regulation of miRNA-target genes in FECD and to describe a potential epigenetic 51 biomarker for the treatment of FECD patients. 52 53

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

Pan

Weisenberger

Zheng

et al. 2019

Preprint

Self Cite

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“…Following a comprehensive systematic review of the literature, this study found that the role of methylation in ophthalmic disease has been evaluated in histone methylation marks,41–43 gene body and promoter regions,44–53 and miRNAs,54 in the following rare ophthalmic conditions:…”

Section: Discussionmentioning

confidence: 99%

Systematic review of differential methylation in rare ophthalmic diseases

et al. 2019

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Rare ophthalmic diseases have a devastating impact on a patient’s vision and consequently negatively affect their independence, ability to work and overall quality of life. Methylation is an important emerging biomarker of disease and may improve understanding of rare ophthalmic disorders. This systematic review sought to identify and evaluate literature on methylation and rare ophthalmic disease. MEDLINE, EMBASE, PubMed, Cochrane Database of Systematic Reviews and grey literature resources were searched for publications prior to 20 August 2019. Articles written in English which featured key terms such as ‘methylation’ and rare ophthalmic diseases were included. Titles, abstracts, keywords and full texts of publications were screened, as well as reference lists for reverse citations and Web of Science ‘cited reference search’ for forward citation searching. Study characteristics were extracted, and methodological rigour appraised using a standardised template. Fourteen articles were selected for full inclusion. Rare ophthalmic conditions include congenital fibrosis of extraocular muscles, retinitis pigmentosa, Fuchs endothelial corneal dystrophy, granular corneal dystrophy, choroideraemia, brittle cornea syndrome, retinopathy of prematurity, keratoconus and congenital cataracts. Outcomes include identification of methylation as contributor to disease and identification of potential novel therapeutic targets. The studies included were heterogeneous with no scope for meta-analysis following review; a narrative synthesis was undertaken. Differential methylation has been identified in a small number of rare ophthalmic diseases and few studies have been performed to date. Further multiomic research will improve understanding of rare eye diseases and hopefully lead to improved provision of diagnostic/prognostic biomarkers, and help identify novel therapeutic targets.

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DNA methylation changes and increased mRNA expression of coagulation proteins, factor V and thrombomodulin in Fuchs endothelial corneal dystrophy

Westin

Landfors

Giannopoulos

et al. 2023

Cell. Mol. Life Sci.

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Late-onset Fuchs endothelial corneal dystrophy (FECD) is a disease affecting the corneal endothelium (CE), associated with a cytosine-thymine-guanine repeat expansion at the CTG18.1 locus in the transcription factor 4 (TCF4) gene. It is unknown whether CTG18.1 expansions affect global methylation including TCF4 gene in CE or whether global CE methylation changes at advanced age. Using genome-wide DNA methylation array, we investigated methylation in CE from FECD patients with CTG18.1 expansions and studied the methylation in healthy CE at different ages. The most revealing DNA methylation findings were analyzed by gene expression and protein analysis. 3488 CpGs had significantly altered methylation pattern in FECD though no substantial changes were found in TCF4. The most hypermethylated site was in a predicted promoter of aquaporin 1 (AQP1) gene, and the most hypomethylated site was in a predicted promoter of coagulation factor V (F5 for gene, FV for protein). In FECD, AQP1 mRNA expression was variable, while F5 gene expression showed a ~ 23-fold increase. FV protein was present in both healthy and affected CE. Further gene expression analysis of coagulation factors interacting with FV revealed a ~ 34-fold increase of thrombomodulin (THBD). THBD protein was detected only in CE from FECD patients. Additionally, we observed an age-dependent hypomethylation in elderly healthy CE.Thus, tissue-specific genome-wide and gene-specific methylation changes associated with altered gene expression were discovered in FECD. TCF4 pathological methylation in FECD because of CTG18.1 expansion was ruled out.

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Comprehensive characterization of DNA methylation changes in Fuchs endothelial corneal dystrophy

Cited by 28 publications

References 70 publications

Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

Systematic review of differential methylation in rare ophthalmic diseases

DNA methylation changes and increased mRNA expression of coagulation proteins, factor V and thrombomodulin in Fuchs endothelial corneal dystrophy

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