Cfp1 Controls Cardiomyocyte Maturation by Modifying Histone H3K4me3 of Structural, Metabolic, and Contractile Related Genes

  • Adv Sci (Weinh). 2024 Jan 9:e2305992. doi: 10.1002/advs.202305992.
Changzhu Li  1 ,  Yang Zhang  1 ,  Jingling Shen  2 ,  Hairong Bao  1 ,  Yue Zhao  1 ,  Desheng Li  1 ,  Sijia Li  1 ,  Yining Liu  1 ,  Jiming Yang  1 ,  Zhiwen Zhou  1 ,  Kangyi Gao  1 ,  Lexin Zhao  1 ,  Yao Pei  1 ,  Yanjie Lu  1 ,  Zhenwei Pan  1  3  4 ,  Benzhi Cai  1
Affiliations
  • 1. Department of Pharmacology (State Key Laboratory of Frigid Zone Cardiovascular Disease, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150086, P. R. China.
  • 2. Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, 2019 Research Unit 070, Harbin, Heilongjiang, 150086, P. R. China.
  • 3. Institute of Life Sciences, College of Life and Environmental Sciences, Wenzhou University, Wenzhou, 325035, P. R. China.
  • 4. Key Laboratory of Cell Transplantation, The First Affiliated Hospital, Harbin Medical University, P. R. China.
PMID: 38196272 DOI: 10.1002/advs.202305992
Abstract

Cardiomyocyte maturation is the final stage of heart development, and abnormal cardiomyocyte maturation will lead to serious heart diseases. CXXC Zinc Finger Protein 1 (Cfp1), a key epigenetic factor in multi-lineage cell development, remains underexplored in its influence on cardiomyocyte maturation. This study investigates the role and mechanisms of Cfp1 in this context. Cardiomyocyte-specific Cfp1 knockout (Cfp1-cKO) mice died within 4 weeks of birth. Cardiomyocytes derived from Cfp1-cKO mice showed an inhibited maturation phenotype, characterized by structural, metabolic, contractile, and cell cycle abnormalities. In contrast, cardiomyocyte-specific Cfp1 transgenic (Cfp1-TG) mice and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) overexpressing Cfp1 displayed a more mature phenotype. Mechanistically, deficiency of Cfp1 led to a reduction in trimethylation on lysine 4 of histone H3 (H3K4me3) modification, accompanied by the formation of ectopic H3K4me3. Furthermore, Cfp1 deletion decreased the level of H3K4me3 modification in adult genes and increased the level of H3K4me3 modification in fetal genes. Collectively, Cfp1 modulates the expression of genes crucial to cardiomyocyte maturation by regulating histone H3K4me3 modification, thereby intricately influencing the maturation process. This study implicates Cfp1 as an important molecule regulating cardiomyocyte maturation, with its dysfunction strongly linked to cardiac disease.

Keywords
Cfp1; H3K4me3; cardiomyocyte maturation; hiPSC-CMs.
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