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07:34
A Method to Study de novo Formation of Chromatin Domains
Published on: August 23, 2019
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Gene-repressing epigenetic reader EED unexpectedly enhances cyclinD1 gene activation.
Mengxue Zhang1, Jing Li1, Qingwei Wang1
1Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Molecular Therapy. Nucleic Acids
|March 16, 2023
Summary
Embryonic ectoderm development (EED) unexpectedly activates the CCND1 gene, promoting vascular smooth muscle cell proliferation and neointima formation. Inhibiting EED reduced neointima in vivo, suggesting a new therapeutic target for stenotic diseases.
Area of Science:
- Epigenetics
- Vascular Biology
- Cell Proliferation
Background:
- Vascular smooth muscle cell (SMC) proliferation drives neointima formation in stenotic diseases.
- Histone marks H3K27me3 (repression) and H3K27ac (activation) regulate gene expression.
- Embryonic ectoderm development (EED) is a canonical repressor, reading H3K27me3.
Purpose of the Study:
- To investigate the role of EED in vascular smooth muscle cell proliferation and neointima formation.
- To elucidate the mechanism by which EED influences gene expression, particularly CCND1.
Main Methods:
- Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) to assess protein-DNA interactions.
- Co-immunoprecipitation to study protein-protein interactions.
- Pharmacological inhibition of EED and BRD4.
- In vivo studies using rat carotid artery injury model and analysis of human neointimal lesions.
Main Results:
- EED overexpression increased CCND1 mRNA in SMCs, contradicting its known repressive function.
- EED co-immunoprecipitated with BRD4, and they co-occupied CCND1 and P57 gene promoters.
- EED inhibition reduced angioplasty-induced neointima formation and cyclinD1 levels in vivo.
Conclusions:
- EED unexpectedly activates the pro-proliferative gene CCND1, likely through cooperation with BRD4.
- This EED-BRD4 interaction represses anti-proliferative P57, promoting SMC proliferation.
- Targeting EED offers a novel epigenetic strategy for treating neointimal hyperplastic disorders.
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