Epigenetic Repression of Chloride Channel Accessory 2 Transcription in Cardiac Fibroblast: Implication in Cardiac Fibrosis

Cardiac fibrosis is a key pathophysiological process that contributes to heart failure. Cardiac resident fibroblasts, exposed to various stimuli, are able to trans-differentiate into myofibroblasts and mediate the pro-fibrogenic response in the heart. The present study aims to investigate the mechan...

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Autores principales:	Tinghui Shao, Yujia Xue, Mingming Fang
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	transcriptional regulation epigenetics histone deacetylation histone deacetylase cardiac fibroblast myocardial fibrosis Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/0a76694e0c73473fb6ad51e0e23ec691
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spelling	oai:doaj.org-article:0a76694e0c73473fb6ad51e0e23ec6912021-11-12T06:07:13ZEpigenetic Repression of Chloride Channel Accessory 2 Transcription in Cardiac Fibroblast: Implication in Cardiac Fibrosis2296-634X10.3389/fcell.2021.771466https://doaj.org/article/0a76694e0c73473fb6ad51e0e23ec6912021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.771466/fullhttps://doaj.org/toc/2296-634XCardiac fibrosis is a key pathophysiological process that contributes to heart failure. Cardiac resident fibroblasts, exposed to various stimuli, are able to trans-differentiate into myofibroblasts and mediate the pro-fibrogenic response in the heart. The present study aims to investigate the mechanism whereby transcription of chloride channel accessory 2 (Clca2) is regulated in cardiac fibroblast and its potential implication in fibroblast-myofibroblast transition (FMyT). We report that Clca2 expression was down-regulated in activated cardiac fibroblasts (myofibroblasts) compared to quiescent cardiac fibroblasts in two different animal models of cardiac fibrosis. Clca2 expression was also down-regulated by TGF-β, a potent inducer of FMyT. TGF-β repressed Clca2 expression at the transcriptional level likely via the E-box element between −516 and −224 of the Clca2 promoter. Further analysis revealed that Twist1 bound directly to the E-box element whereas Twist1 depletion abrogated TGF-β induced Clca2 trans-repression. Twist1-mediated Clca2 repression was accompanied by erasure of histone H3/H4 acetylation from the Clca2 promoter. Mechanistically Twist1 interacted with HDAC1 and recruited HDAC1 to the Clca2 promoter to repress Clca2 transcription. Finally, it was observed that Clca2 over-expression attenuated whereas Clca2 knockdown enhanced FMyT. In conclusion, our data demonstrate that a Twist1-HDAC1 complex represses Clca2 transcription in cardiac fibroblasts, which may contribute to FMyT and cardiac fibrosis.Tinghui ShaoYujia XueMingming FangMingming FangFrontiers Media S.A.articletranscriptional regulationepigeneticshistone deacetylationhistone deacetylasecardiac fibroblastmyocardial fibrosisBiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	transcriptional regulation epigenetics histone deacetylation histone deacetylase cardiac fibroblast myocardial fibrosis Biology (General) QH301-705.5
spellingShingle	transcriptional regulation epigenetics histone deacetylation histone deacetylase cardiac fibroblast myocardial fibrosis Biology (General) QH301-705.5 Tinghui Shao Yujia Xue Mingming Fang Mingming Fang Epigenetic Repression of Chloride Channel Accessory 2 Transcription in Cardiac Fibroblast: Implication in Cardiac Fibrosis
description	Cardiac fibrosis is a key pathophysiological process that contributes to heart failure. Cardiac resident fibroblasts, exposed to various stimuli, are able to trans-differentiate into myofibroblasts and mediate the pro-fibrogenic response in the heart. The present study aims to investigate the mechanism whereby transcription of chloride channel accessory 2 (Clca2) is regulated in cardiac fibroblast and its potential implication in fibroblast-myofibroblast transition (FMyT). We report that Clca2 expression was down-regulated in activated cardiac fibroblasts (myofibroblasts) compared to quiescent cardiac fibroblasts in two different animal models of cardiac fibrosis. Clca2 expression was also down-regulated by TGF-β, a potent inducer of FMyT. TGF-β repressed Clca2 expression at the transcriptional level likely via the E-box element between −516 and −224 of the Clca2 promoter. Further analysis revealed that Twist1 bound directly to the E-box element whereas Twist1 depletion abrogated TGF-β induced Clca2 trans-repression. Twist1-mediated Clca2 repression was accompanied by erasure of histone H3/H4 acetylation from the Clca2 promoter. Mechanistically Twist1 interacted with HDAC1 and recruited HDAC1 to the Clca2 promoter to repress Clca2 transcription. Finally, it was observed that Clca2 over-expression attenuated whereas Clca2 knockdown enhanced FMyT. In conclusion, our data demonstrate that a Twist1-HDAC1 complex represses Clca2 transcription in cardiac fibroblasts, which may contribute to FMyT and cardiac fibrosis.
format	article
author	Tinghui Shao Yujia Xue Mingming Fang Mingming Fang
author_facet	Tinghui Shao Yujia Xue Mingming Fang Mingming Fang
author_sort	Tinghui Shao
title	Epigenetic Repression of Chloride Channel Accessory 2 Transcription in Cardiac Fibroblast: Implication in Cardiac Fibrosis
title_short	Epigenetic Repression of Chloride Channel Accessory 2 Transcription in Cardiac Fibroblast: Implication in Cardiac Fibrosis
title_full	Epigenetic Repression of Chloride Channel Accessory 2 Transcription in Cardiac Fibroblast: Implication in Cardiac Fibrosis
title_fullStr	Epigenetic Repression of Chloride Channel Accessory 2 Transcription in Cardiac Fibroblast: Implication in Cardiac Fibrosis
title_full_unstemmed	Epigenetic Repression of Chloride Channel Accessory 2 Transcription in Cardiac Fibroblast: Implication in Cardiac Fibrosis
title_sort	epigenetic repression of chloride channel accessory 2 transcription in cardiac fibroblast: implication in cardiac fibrosis
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/0a76694e0c73473fb6ad51e0e23ec691
work_keys_str_mv	AT tinghuishao epigeneticrepressionofchloridechannelaccessory2transcriptionincardiacfibroblastimplicationincardiacfibrosis AT yujiaxue epigeneticrepressionofchloridechannelaccessory2transcriptionincardiacfibroblastimplicationincardiacfibrosis AT mingmingfang epigeneticrepressionofchloridechannelaccessory2transcriptionincardiacfibroblastimplicationincardiacfibrosis AT mingmingfang epigeneticrepressionofchloridechannelaccessory2transcriptionincardiacfibroblastimplicationincardiacfibrosis
_version_	1718431149929267200

Epigenetic Repression of Chloride Channel Accessory 2 Transcription in Cardiac Fibroblast: Implication in Cardiac Fibrosis

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