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Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

Homeostatic maintenance of corneal endothelial cells is essential for maintenance of corneal deturgescence and transparency. In Fuchs endothelial corneal dystrophy (FECD), an accelerated loss and dysfunction of endothelial cells leads to progressively severe visual impairment. An abnormal accumulati...

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Autores principales: Pan, Peipei, Weisenberger, Daniel J., Zheng, Siyu, Wolf, Marie, Hwang, David G., Rose-Nussbaumer, Jennifer R., Jurkunas, Ula V., Chan, Matilda F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841734/
https://www.ncbi.nlm.nih.gov/pubmed/31705138
http://dx.doi.org/10.1038/s41598-019-52727-z
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author Pan, Peipei
Weisenberger, Daniel J.
Zheng, Siyu
Wolf, Marie
Hwang, David G.
Rose-Nussbaumer, Jennifer R.
Jurkunas, Ula V.
Chan, Matilda F.
author_facet Pan, Peipei
Weisenberger, Daniel J.
Zheng, Siyu
Wolf, Marie
Hwang, David G.
Rose-Nussbaumer, Jennifer R.
Jurkunas, Ula V.
Chan, Matilda F.
author_sort Pan, Peipei
collection PubMed
description Homeostatic maintenance of corneal endothelial cells is essential for maintenance of corneal deturgescence and transparency. In Fuchs endothelial corneal dystrophy (FECD), an accelerated loss and dysfunction of endothelial cells leads to progressively severe visual impairment. An abnormal accumulation of extracellular matrix (ECM) is a distinctive hallmark of the disease, however the molecular pathogenic mechanisms underlying this phenomenon are not fully understood. Here, we investigate genome-wide and sequence-specific DNA methylation changes of miRNA genes in corneal endothelial samples from FECD patients. We discover that miRNA gene promoters are frequent targets of aberrant DNA methylation in FECD. More specifically, miR-199B is extensively hypermethylated and its mature transcript miR-199b-5p was previously found to be almost completely silenced in FECD. Furthermore, we find that miR-199b-5p directly and negatively regulates Snai1 and ZEB1, two zinc finger transcription factors that lead to increased ECM deposition in FECD. Taken together, these findings suggest a novel epigenetic regulatory mechanism of matrix protein production by corneal endothelial cells in which miR-199B hypermethylation leads to miR-199b-5p downregulation and thereby the increased expression of its target genes, including Snai1 and ZEB1. Our results support miR-199b-5p as a potential therapeutic target to prevent or slow down the progression of FECD disease.
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spelling pubmed-68417342019-11-14 Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy Pan, Peipei Weisenberger, Daniel J. Zheng, Siyu Wolf, Marie Hwang, David G. Rose-Nussbaumer, Jennifer R. Jurkunas, Ula V. Chan, Matilda F. Sci Rep Article Homeostatic maintenance of corneal endothelial cells is essential for maintenance of corneal deturgescence and transparency. In Fuchs endothelial corneal dystrophy (FECD), an accelerated loss and dysfunction of endothelial cells leads to progressively severe visual impairment. An abnormal accumulation of extracellular matrix (ECM) is a distinctive hallmark of the disease, however the molecular pathogenic mechanisms underlying this phenomenon are not fully understood. Here, we investigate genome-wide and sequence-specific DNA methylation changes of miRNA genes in corneal endothelial samples from FECD patients. We discover that miRNA gene promoters are frequent targets of aberrant DNA methylation in FECD. More specifically, miR-199B is extensively hypermethylated and its mature transcript miR-199b-5p was previously found to be almost completely silenced in FECD. Furthermore, we find that miR-199b-5p directly and negatively regulates Snai1 and ZEB1, two zinc finger transcription factors that lead to increased ECM deposition in FECD. Taken together, these findings suggest a novel epigenetic regulatory mechanism of matrix protein production by corneal endothelial cells in which miR-199B hypermethylation leads to miR-199b-5p downregulation and thereby the increased expression of its target genes, including Snai1 and ZEB1. Our results support miR-199b-5p as a potential therapeutic target to prevent or slow down the progression of FECD disease. Nature Publishing Group UK 2019-11-08 /pmc/articles/PMC6841734/ /pubmed/31705138 http://dx.doi.org/10.1038/s41598-019-52727-z Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Pan, Peipei
Weisenberger, Daniel J.
Zheng, Siyu
Wolf, Marie
Hwang, David G.
Rose-Nussbaumer, Jennifer R.
Jurkunas, Ula V.
Chan, Matilda F.
Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy
title Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy
title_full Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy
title_fullStr Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy
title_full_unstemmed Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy
title_short Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy
title_sort aberrant dna methylation of mirnas in fuchs endothelial corneal dystrophy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841734/
https://www.ncbi.nlm.nih.gov/pubmed/31705138
http://dx.doi.org/10.1038/s41598-019-52727-z
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