Mapping Long-Range Chromatin Interactions and Gene Control Mechanisms in Human Heart Failure

Article Impact Level: HIGH
Data Quality: STRONG
Summary of  Science  https://doi.org/10.1126/science.ady6893 
Dr. Yang Xie  et al.

Points

Researchers from UC San Diego mapped multiomic genome regulation across 750,000 single heart cells from 36 individuals with and without end-stage heart failure.
High-resolution multiomic analysis delineated 12 major cardiac cell types and dozens of distinct subpopulations across all four chambers of normal and failing human hearts.
Tissue remodeling in failing hearts involved transcriptomic shifts in over 10,000 genes along with altered chromatin accessibility across more than 50,000 specific genomic regions.
Genome-wide association data confirmed that noncoding disease variants act via long-range DNA interactions primarily within regulatory regions active in cardiomyocytes.
Identifying intermediate cell transitions from healthy to diseased phenotypes provides a mechanistic framework to develop precision drug targets for heart failure intervention.

Summary

Single-cell multiomic profiles and chromatin structures across healthy and failing human heart tissue to elucidate cell-type-specific gene-regulatory breakdown during heart failure. More than 85% of heart failure-associated genetic variants identified in genome-wide association studies reside within noncoding genomic regions, complicating the identification of causative mechanisms. The research team sought to integrate multi-layered genomic regulation data across distinct cardiac cell lineages to map noncoding regulatory elements, chromatin accessibility, and long-range DNA interactions in normal and end-stage failing myocardium.

Using single-cell multiomic profiling of cardiac tissue harvested from 36 individuals with and without heart failure, the researchers characterized genome organization across more than 750,000 individual heart cells. Analysis resolved 12 major cardiac cell types and dozens of subpopulations spanning all four heart chambers. In failing hearts, transcriptomic and epigenomic remodeling was characterized by over 10,000 genes with altered expression levels and more than 50,000 genomic regions displaying altered chromatin accessibility. Compositional shifts included significant reductions in functional cardiomyocytes accompanied by expansion of activated fibroblasts, myofibroblasts, and infiltrating immune cell populations.

Integration with genome-wide association datasets revealed that disease-associated noncoding variants are overwhelmingly concentrated in cell-type-specific regulatory elements, acting through long-range chromatin interactions to modulate expression predominantly within cardiomyocytes. The identification of distinct intermediate cell states during the transition of healthy cardiomyocytes and quiescent fibroblasts into pathological phenotypes provides actionable targets for early intervention. These findings establish a comprehensive multiomic framework linking noncoding genetic risk to specific cell-type regulatory networks, identifying cardiomyocyte-specific regulatory elements as high-priority therapeutic targets for precision medicine in heart failure.

Link to the article: https://www.science.org/doi/10.1126/science.ady6893

References

Xie, Y., Tucciarone, L., Farah, E. N., Chang, L., Yang, Q., Shankar, T. S., Elison, W., Tran, S., Djulamsah, J., Lie, A., Loe, T., Holman, A. R., Corban, S., Buchanan, J., Mamde, S., Zhou, H., Elgamal, R. M., Tseliou, E., Huang, V., … Chi, N. C. (2026). Single-cell multiomics and chromatin structure reveal gene-regulatory dynamics in heart failure. Science, 393(6809), eady6893. https://doi.org/10.1126/science.ady6893