Single-cell multiomics and chromatin structure reveal gene-regulatory dynamics in heart failure.

Summary

This study builds a multimodal, cell type–resolved regulatory atlas of failing versus nonfailing human hearts, integrating scRNA-seq, chromatin accessibility, histone marks, and 3D chromatin organization. It identifies dynamic gene-regulatory programs in cardiomyocytes and fibroblasts and links enhancer–gene maps to genetic risk, enabling cell type–targeted therapeutic hypotheses in heart failure.

Key Findings

• Constructed a multimodal atlas (transcriptome, chromatin accessibility, histone marks, 3D organization) across 36 human hearts (13 nonfailing, 23 failing).
• Identified dynamic, cell type–specific gene-regulatory programs in cardiomyocytes and fibroblasts during heart failure.
• Mapped cell type–specific enhancer–gene interactions and connected them to likely causal genetic contributors from association data.

Clinical Implications

While not immediately practice-changing, these maps prioritize cell type–specific pathways and enhancer–gene links that can be leveraged for target selection, interpretation of GWAS signals, and development of cardiomyocyte- or fibroblast-directed therapies.

Limitations

• Cross-sectional analysis limits causal inference and temporal dynamics of disease progression.
• Sample size, tissue procurement variability, and batch effects may influence rare cell-state detection.

Future Directions

Leverage enhancer–gene maps for perturbation studies, prioritize cell type–specific targets for drug discovery, and validate in longitudinal tissue and human iPSC-derived models.