Sulfotransferases Restrict Epigenetic Plasticity in Heart Regeneration

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Summary of  Nature Communications. https://doi.org/10.1038/s41467-026-75583-8  
Dr. Michaela R. Romero  et al.

Points

Researchers identified carbohydrate sulfotransferase 7 as a key glycosylation-associated protein that reinforces somatic cell identity and blocks direct cardiac reprogramming.
Downstream signaling governed by the cell membrane receptor CD44 and transcription factor JUNB works in concert with CHST7 to restrict chromatin access at cardiac-specific genetic loci.
Genetic deletion of CD44 in CHST7-overexpressing cells improved cardiac reprogramming efficiency by 47% compared with controls maintaining normal receptor expression levels.
Epigenetic mapping demonstrated that this signaling network prevents key reprogramming factors like MEF2C from accessing closed chromatin regions required for lineage conversion.
Pharmacological inhibition of the downstream kinase PIP4K2C combined with reprogramming therapy restored left ventricular ejection fraction to 58.6% in post-infarction mouse models.

Summary

Molecular barriers that enforce somatic cell identity and restrict direct cardiac reprogramming for myocardial repair. While adult mammalian cardiomyocytes lack endogenous regenerative capacity, reprogramming cardiac fibroblasts into functional heart cells remains challenging due to active epigenetic cell fate barriers. Led by researchers at Sanford Burnham Prebys and Johns Hopkins University, the investigation sought to elucidate how glycosylation-associated genes, specifically carbohydrate sulfotransferases, safeguard cell identity and block reprogramming factors such as myocyte enhancer factor 2C (MEF2C).

Using integrated RNA-sequencing and ATAC-sequencing analyses, investigators identified carbohydrate sulfotransferase 7 (CHST7) as a primary barrier to cell fate conversion in mouse and human cells. Mechanistically, CHST7 acts through the cell membrane receptor CD44 to modulate the transcription factor JUNB. In CD44-deficient cells overexpressing CHST7, reprogramming efficiency increased by 47% compared to CD44-intact controls, demonstrating that CD44 mediates CHST7-driven identity stabilization. Epigenetic profiling revealed that the CHST7-CD44-JUNB axis maintains open chromatin at JUNB- and CTCF-enriched loci to reinforce fibroblast identity while locking access to MEF2C-enriched cardiac locus regions.

Downstream target screening identified phosphatidylinositol-5-phosphate 4-kinase type 2 gamma (PIP4K2C) as a key effector of this pathway. In a mouse model of myocardial infarction, combining PIP4K2C inhibition with standard cardiac reprogramming significantly enhanced functional recovery. One month post-infarction, mice receiving the combination therapy maintained a mean left ventricular ejection fraction of 58.6%, compared with 24.9% in the reprogramming-only control group. The findings establish the CHST7-CD44-PIP4K2C signaling cascade as a major epigenetic barrier to cellular conversion, identifying novel pharmacological targets to improve therapeutic heart regeneration.

Link to the article: https://www.nature.com/articles/s41467-026-75583-8

References

Romero, M. R., Murphy, S., Chang, Y.-L., Lamba, A., Ancel, S., Llorente, A., Marchant, J., Huang, C.-T., Kumsta, C., Andersen, P., Ranade, S., Mahmoud, A. I., Kwon, C., Freeze, H. H., Adams, P. D., Sacco, A., Ranek, M. J., Emerling, B. M., Wang, Y. X., & Colas, A. R. (2026). Sulfotransferase signaling sustains fibroblast identity and antagonizes therapeutic cardiac reprogramming. Nature Communications. https://doi.org/10.1038/s41467-026-75583-8