PUBLICATION
Cross-species comparison reveals that Hmga1 reduces H3K27me3 levels to promote cardiomyocyte proliferation and cardiac regeneration
- Authors
- Bouwman, M., de Bakker, D.E.M., Honkoop, H., Giovou, A.E., Versteeg, D., Boender, A.R., Nguyen, P.D., Slotboom, M., Colquhoun, D., Vigil-Garcia, M., Kooijman, L., Janssen, R., Hooijkaas, I.B., Günthel, M., Visser, K.J., Klerk, M., Zentilin, L., Giacca, M., Kaslin, J., Boink, G.J.J., van Rooij, E., Christoffels, V.M., Bakkers, J.
- ID
- ZDB-PUB-250109-134
- Date
- 2025
- Source
- Nature cardiovascular research 4(1): 64-82 (Journal)
- Registered Authors
- Bakkers, Jeroen, Kaslin, Jan
- Keywords
- none
- Datasets
- GEO:GSE241390, GEO:GSE241158, GEO:GSE241157, GEO:GSE241156, GEO:GSE241159
- MeSH Terms
-
- Myocytes, Cardiac*/metabolism
- Cell Proliferation*
- HMGA1a Protein*/genetics
- HMGA1a Protein*/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Species Specificity
- Methylation
- Regeneration*/physiology
- Cells, Cultured
- Mice, Inbred C57BL
- Chromatin Assembly and Disassembly
- Zebrafish*
- Animals
- Heart Injuries/metabolism
- Heart Injuries/pathology
- Disease Models, Animal
- Mice
- Histones*/metabolism
- PubMed
- 39747457 Full text @ Nat Cardiovasc Res
Citation
Bouwman, M., de Bakker, D.E.M., Honkoop, H., Giovou, A.E., Versteeg, D., Boender, A.R., Nguyen, P.D., Slotboom, M., Colquhoun, D., Vigil-Garcia, M., Kooijman, L., Janssen, R., Hooijkaas, I.B., Günthel, M., Visser, K.J., Klerk, M., Zentilin, L., Giacca, M., Kaslin, J., Boink, G.J.J., van Rooij, E., Christoffels, V.M., Bakkers, J. (2025) Cross-species comparison reveals that Hmga1 reduces H3K27me3 levels to promote cardiomyocyte proliferation and cardiac regeneration. Nature cardiovascular research. 4(1):64-82.
Abstract
In contrast to adult mammalian hearts, the adult zebrafish heart efficiently replaces cardiomyocytes lost after injury. Here we reveal shared and species-specific injury response pathways and a correlation between Hmga1, an architectural non-histone protein, and regenerative capacity, as Hmga1 is required and sufficient to induce cardiomyocyte proliferation and required for heart regeneration. In addition, Hmga1 was shown to reactivate developmentally silenced genes, likely through modulation of H3K27me3 levels, poising them for a pro-regenerative gene program. Furthermore, AAV-mediated Hmga1 expression in injured adult mouse hearts led to controlled cardiomyocyte proliferation in the border zone and enhanced heart function, without cardiomegaly and adverse remodeling. Histone modification mapping in mouse border zone cardiomyocytes revealed a similar modulation of H3K27me3 marks, consistent with findings in zebrafish. Our study demonstrates that Hmga1 mediates chromatin remodeling and drives a regenerative program, positioning it as a promising therapeutic target to enhance cardiac regeneration after injury.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping