Genetic dissection of cell type–specific congenital heart disease variants reveals ETS1 control of vascular smooth muscle cell fate
6 affiliations
- 1Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou 510280, China.
- 2Affiliated Hospital, Guangdong Medical University, Renmin Road South, Xiashan District, Zhanjiang 524001, Guangdong, China.
- 3Department of Physiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
- 4Department of Cardiology, Heart Center, First People’s Hospital of Shunde, Southern Medical University, Shunde District, Foshan 528300, China.
- 5School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China.
- 6Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 10087, China.
Abstract
Numerous congenital heart disease (CHD) risk variants lie in cis-regulatory elements, yet the impact of variants in repressed and bivalent chromatin on cell type–specific heart development is unclear. Here, we generated a single-cell multiomic atlas of human cardiac differentiation by jointly profiling H3K27ac, H3K27me3, H3K4me3, and transcriptomes in individual cells, classifying cis-regulatory elements into six chromatin states, enabling prioritization of 610 CHD-associated noncoding variants enriched in lineage- and state-specific regulatory elements, including repressive and bivalent regions. CRISPR knockin of selected variants perturbed nearby gene expression and impaired cardiac differentiation. Dissection of a Polycomb-marked variant near ETS1 (ETS proto-oncogene 1) revealed local H3K27me3 loss, H3K27ac gain, and ETS1 up-regulation, which redirects differentiation toward second-heart-field progenitors with epithelial characteristics at early stages and, ultimately, highly migratory ETS1+ vascular smooth muscle cells. Together, our work establishes a single-cell chromatin-state framework for interpreting noncoding CHD risk variants and uncovers an ETS1-driven program linking Polycomb-deregulated noncoding variation to aberrant vascular smooth muscle fate commitment during human cardiogenesis.
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BibTeX
@article{li2026genetic,
title = {{Genetic dissection of cell type–specific congenital heart disease variants reveals ETS1 control of vascular smooth muscle cell fate}},
author = {Xin Li and Mingzhu Fu and Shengtao Jia and Zhenwei Wu and Long Pang and Ke Xiong and Yujun Wang and Wen Li and Aibin He and Shanshan Ai},
journal = {Science Advances},
year = {2026},
month = nov,
doi = {10.1126/sciadv.aeg4687},
url = {https://www.science.org/doi/abs/10.1126/sciadv.aeg4687},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Genetic dissection of cell type–specific congenital heart disease variants reveals ETS1 control of vascular smooth muscle cell fate
AU - Xin Li
AU - Mingzhu Fu
AU - Shengtao Jia
AU - Zhenwei Wu
AU - Long Pang
AU - Ke Xiong
AU - Yujun Wang
AU - Wen Li
AU - Aibin He
AU - Shanshan Ai
PY - 2026
DA - 2026/11/04
JO - Science Advances
DO - 10.1126/sciadv.aeg4687
UR - https://www.science.org/doi/abs/10.1126/sciadv.aeg4687
AB - Numerous congenital heart disease (CHD) risk variants lie in cis-regulatory elements, yet the impact of variants in repressed and bivalent chromatin on cell type–specific heart development is unclear. Here, we generated a single-cell multiomic atlas of human cardiac differentiation by jointly profiling H3K27ac, H3K27me3, H3K4me3, and transcriptomes in individual cells, classifying cis-regulatory elements into six chromatin states, enabling prioritization of 610 CHD-associated noncoding variants enriched in lineage- and state-specific regulatory elements, including repressive and bivalent regions. CRISPR knockin of selected variants perturbed nearby gene expression and impaired cardiac differentiation. Dissection of a Polycomb-marked variant near ETS1 (ETS proto-oncogene 1) revealed local H3K27me3 loss, H3K27ac gain, and ETS1 up-regulation, which redirects differentiation toward second-heart-field progenitors with epithelial characteristics at early stages and, ultimately, highly migratory ETS1+ vascular smooth muscle cells. Together, our work establishes a single-cell chromatin-state framework for interpreting noncoding CHD risk variants and uncovers an ETS1-driven program linking Polycomb-deregulated noncoding variation to aberrant vascular smooth muscle fate commitment during human cardiogenesis.
SN - 2375-2548
ER -