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Angioplasty induces epigenomic remodeling in injured arteries

Mengxue Zhang, Go Urabe, Hatice Gulcin Ozer, Xiujie Xie, Amy Webb, Takuro Shirasu, Jing Li, Renzhi Han, K Craig Kent, View ORCID ProfileBowen Wang  Correspondence email, View ORCID ProfileLian-Wang Guo  Correspondence email
Mengxue Zhang
1Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, USA
Roles: Data curation, Investigation
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Go Urabe
1Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, USA
Roles: Data curation, Formal analysis
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Hatice Gulcin Ozer
2Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA
Roles: Formal analysis, Investigation, Visualization
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Xiujie Xie
1Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, USA
Roles: Data curation, Methodology
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Amy Webb
2Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA
Roles: Formal analysis, Investigation, Visualization
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Takuro Shirasu
1Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, USA
Roles: Data curation
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Jing Li
1Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, USA
Roles: Data curation
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Renzhi Han
3Department of Surgery, College of Medicine, The Ohio State University, Columbus, OH, USA
Roles: Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Gene editing methodology
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K Craig Kent
1Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, USA
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Bowen Wang
1Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, USA
Roles: Conceptualization, Formal analysis, Investigation, Writing—review and editing
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  • ORCID record for Bowen Wang
  • For correspondence: bw2pw@virginia.edu
Lian-Wang Guo
1Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, USA
4Department of Molecular Physiology and Biological Physics, School of Medicine, University of Virginia, Charlottesville, VA, USA
5Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA
Roles: Conceptualization, Supervision, Funding acquisition, Project administration, Writing—original draft, review, and editing
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  • For correspondence: lg8zr@virginia.edu
Published 15 February 2022. DOI: 10.26508/lsa.202101114
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Abstract

Neointimal hyperplasia/proliferation (IH) is the primary etiology of vascular stenosis. Epigenomic studies concerning IH have been largely confined to in vitro models, and IH-underlying epigenetic mechanisms remain poorly understood. This study integrates information from in vivo epigenomic mapping, conditional knockout, gene transfer and pharmacology in rodent models of IH. The data from injured (IH-prone) rat arteries revealed a surge of genome-wide occupancy by histone-3 lysine-27 trimethylation (H3K27me3), a gene-repression mark. This was unexpected in the traditional view of prevailing post-injury gene activation rather than repression. Further analysis illustrated a shift of H3K27me3 enrichment to anti-proliferative genes, from pro-proliferative genes where gene-activation mark H3K27ac(acetylation) accumulated instead. H3K27ac and its reader BRD4 (bromodomain protein) co-enriched at Ezh2; conditional BRD4 knockout in injured mouse arteries reduced H3K27me3 and its writer EZH2, which positively regulated another pro-IH chromatin modulator UHRF1. Thus, results uncover injury-induced loci-specific H3K27me3 redistribution in the epigenomic landscape entailing BRD4→EZH2→UHRF1 hierarchical regulations. Given that these players are pharmaceutical targets, further research may help improve treatments of IH.

  • Received May 5, 2021.
  • Revision received January 25, 2022.
  • Accepted January 26, 2022.
  • © 2022 Zhang et al.
Creative Commons logoCreative Commons logohttps://creativecommons.org/licenses/by/4.0/

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

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Epigenomic remodeling upon neointima formation
Mengxue Zhang, Go Urabe, Hatice Gulcin Ozer, Xiujie Xie, Amy Webb, Takuro Shirasu, Jing Li, Renzhi Han, K Craig Kent, Bowen Wang, Lian-Wang Guo
Life Science Alliance Feb 2022, 5 (5) e202101114; DOI: 10.26508/lsa.202101114

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Epigenomic remodeling upon neointima formation
Mengxue Zhang, Go Urabe, Hatice Gulcin Ozer, Xiujie Xie, Amy Webb, Takuro Shirasu, Jing Li, Renzhi Han, K Craig Kent, Bowen Wang, Lian-Wang Guo
Life Science Alliance Feb 2022, 5 (5) e202101114; DOI: 10.26508/lsa.202101114
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Volume 5, No. 5
May 2022
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