article Open Access (gold) EN 2026-04-06

An integrative single-nucleus multiomic atlas of the human left ventricle identifies gene regulatory network dynamics across cardiac development, aging, and disease

William Gao, Peng Hu, Brittney Wick, Qi Qiu, Hongjie Zhang, Ying Li, Xiangjin Kang, Kenneth Bedi, Maximilian Haeussler, Kotaro Sasaki, Kenneth Margulies, Hao Wu

Genome biology, Vol. 27, Issue 1 (2026)

William Penn University, Penn Center for AIDS Research, University of Pennsylvania, Shanghai Ocean University, University of California, Santa Cruz

DOI: 10.1186/s13059-026-04061-7 PMID: 41937210

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Abstract

BACKGROUND: As the first organ to develop in utero, the human heart undergoes extensive molecular, structural and metabolic remodeling during development and must sustain its function throughout life. RESULTS: We generate an integrated multiomic atlas of human cardiac cells, combining newly generated and publicly available single-nucleus RNA sequencing datasets from 299 donors and single nucleus ATAC-seq datasets from 106 donors. Developmental and disease-associated processes drive far more extensive molecular remodeling than sex-associated or aging-dependent effects. Across nearly all cardiac cell types, developmental and disease-driven changes exhibit strong overlap at both the transcriptomic and epigenomic levels, revealing widespread reactivation of fetal-associated gene programs beyond cardiomyocytes. Both cardiac development and disease show convergent shifts in intercellular communication, including increased TGFβ signaling. Integration of gene expression and chromatin accessibility data reveals putative cell-type-specific transcriptional factors driving fetal reactivation in major cardiac diseases. Spatial transcriptomics data orthogonally identifies localization of this fetal reactivation signature within spatially distinct niches in ischemic and fibrotic zones of acute myocardial infarction. Finally, we construct a cell-type-resolved enhancer-to-gene linkage map that refines the association of dilated and hypertrophic cardiomyopathy genetic risk loci to downstream target genes. CONCLUSIONS: This study presents a comprehensive multimodal, cell-type-resolved atlas of the human heart, providing a foundation for understanding human cardiac gene regulation across the human lifespan and in cardiac diseases.

Topics

Congenital heart defects research 0.82 Cardiac electrophysiology and arrhythmias 0.06 Cardiomyopathy and Myosin Studies 0.03

Field: Biochemistry, Genetics and Molecular Biology · Subfield: Molecular Biology

Keywords

Gene regulatory network,Disease,Ventricle,Human genetics,Gene,Regulator gene

MeSH Terms

Single-Cell Gene Expression AnalysisSingle-Cell Gene Expression AnalysisSingle-Cell Gene Expression AnalysisMultiomicsMultiomicsMultiomicsSpatial TranscriptomicsSpatial Transcriptomics

All Available Versions

Landing page — Genome biology publishedVersion cc-by-nc-nd
Landing page — PubMed publishedVersion
Landing page — DOAJ (DOAJ: Directory of Open Access Journals) submittedVersion
Landing page — PubMed Central submittedVersion other-oa

Citations by Year

2026
1

APA

William Gao, Peng Hu, Brittney Wick, Qi Qiu, Hongjie Zhang, Ying Li, Xiangjin Kang, Kenneth Bedi, Maximilian Haeussler, Kotaro Sasaki, Kenneth Margulies, Hao Wu (2026). An integrative single-nucleus multiomic atlas of the human left ventricle identifies gene regulatory network dynamics across cardiac development, aging, and disease. Genome biology, 27(1). https://doi.org/10.1186/s13059-026-04061-7

MLA

William Gao, et al. "An integrative single-nucleus multiomic atlas of the human left ventricle identifies gene regulatory network dynamics across cardiac development, aging, and disease." Genome biology, vol. 27, no. 1, 2026. https://doi.org/10.1186/s13059-026-04061-7

Chicago

William Gao, Peng Hu, Brittney Wick, Qi Qiu, Hongjie Zhang, Ying Li, Xiangjin Kang, Kenneth Bedi, Maximilian Haeussler, Kotaro Sasaki, Kenneth Margulies, Hao Wu. "An integrative single-nucleus multiomic atlas of the human left ventricle identifies gene regulatory network dynamics across cardiac development, aging, and disease." Genome biology 27, no. 1 (2026). https://doi.org/10.1186/s13059-026-04061-7

BibTeX

@article{gao2026,
  title = { An integrative single-nucleus multiomic atlas of the human left ventricle identifies gene regulatory network dynamics across cardiac development, aging, and disease },
  author = { William Gao and Peng Hu and Brittney Wick and Qi Qiu and Hongjie Zhang and Ying Li and Xiangjin Kang and Kenneth Bedi and Maximilian Haeussler and Kotaro Sasaki and Kenneth Margulies and Hao Wu },
  journal = { Genome biology },
  year = { 2026 },
  volume = { 27 },
  number = { 1 },
  doi = { 10.1186/s13059-026-04061-7 }
}

RIS

TY  - JOUR
TI  - An integrative single-nucleus multiomic atlas of the human left ventricle identifies gene regulatory network dynamics across cardiac development, aging, and disease
AU  - William Gao
AU  - Peng Hu
AU  - Brittney Wick
AU  - Qi Qiu
AU  - Hongjie Zhang
AU  - Ying Li
AU  - Xiangjin Kang
AU  - Kenneth Bedi
AU  - Maximilian Haeussler
AU  - Kotaro Sasaki
AU  - Kenneth Margulies
AU  - Hao Wu
JO  - Genome biology
PY  - 2026
VL  - 27
IS  - 1
DO  - 10.1186/s13059-026-04061-7
ER  -

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3.84

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92%

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158

References

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