Zebrafish Revolution: Discovering Proteins That Awaken Hidden Genes for Cardiac Healing

A protein facilitating repair

The research team found a protein that supports heart recovery in zebrafish. “We compared the zebrafish heart with the mouse heart, which, similar to the human heart, lacks the ability to regenerate,” states Dennis de Bakker, the lead author of the study. “We examined the expression of genes in both damaged and healthy regions of the heart,” he clarifies. “Our results indicated that the gene encoding the Hmga1 protein is active during heart regeneration in zebrafish but inactive in mice. This indicated that Hmga1 is crucial for heart repair.” Generally, the Hmga1 protein is vital during embryonic growth when cells are rapidly proliferating. However, in mature cells, the gene encoding this protein is deactivated.

Removing ‘obstacles’

The researchers delve into the functionality of the Hmga1 protein. “We found that Hmga1 eliminates molecular ‘obstacles’ on chromatin,” explains Mara Bouwman, co-leading author. Chromatin is the organization that contains DNA. When it is densely packed, genes remain inactive. Once it unravels, genes can reactivate. “Hmga1 clears the path, as it were, allowing dormant genes to resume activity,” she adds.

Looking ahead

These revelations open new avenues for secure, targeted regenerative treatments, yet much work lies ahead. “We must refine and evaluate the therapy further before it can be implemented in clinical settings,” claims Bakkers. “The subsequent phase involves testing whether the protein is effective on human heart muscle cells in culture. We are partnering with UMC Utrecht for this effort, and in 2025, the Summit program (DRIVE-RM) will commence to investigate heart regeneration further.”

Citation: Bouwman M, de Bakker DEM, Honkoop H, et al. Cross-species analysis reveals that Hmga1 reduces H3K27me3 levels to enhance cardiomyocyte proliferation and cardiac regeneration. Nat Cardiovasc Res. 2025. doi: 10.1038/s44161-024-00588-9

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