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Kdm7aa Orchestrates an Immunomodulatory Cardiomyocyte Program to Enable Zebrafish Heart Regeneration

Year: 2025

Type: article

Abstract: Myocardial infarction triggers limited repair in adult mammals but robust regeneration in zebrafish. Epigenetic regulation and immune responses are recognized as critical for successful regeneration. However, the molecular links between these processes have not been fully elucidated. By performing single-cell RNA sequencing of zebrafish ventricular cardiomyocytes after injury, we identified a regeneration-induced immunomodulatory cluster that specifically expressed the histone demethylase gene kdm7aa. Functional perturbations, including CRISPR/Cas9-mediated kdm7aa mutation and pharmacological inhibition of Kdm7aa activity using TC-E5002, impaired cardiac regeneration. Bulk RNA sequencing showed that kdm7aa drives an inflammatory transcriptional program, prominently activating chemokines such as cxcl8a and cxcl19 that coordinate immune cell recruitment. Cross-species analyses revealed injury-induced Kdm7a upregulation in regeneration-competent neonatal mouse hearts but not in adult mouse or human hearts. These data identified Kdm7aa as a regeneration-induced epigenetic regulator that enabled cardiomyocytes to adopt a transient immune-activating phenotype, linking histone demethylation to chemokine signaling and suggesting a potential therapeutic strategy to enhance mammalian cardiac repair.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms262010044

Authors: Weibin Lin, Yuan Shi, Jin Tian, Xinru Liu, Fubin Weng, Zekai Wu

Institutions: Fujian Medical University, Fujian Agriculture and Forestry University

Language: English

Topic: Congenital heart defects research

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499