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The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis

Author

Listed:
  • Peilu She

    (East China Normal University
    Southern Medical University)

  • Bangjun Gao

    (East China Normal University)

  • Dongliang Li

    (East China Normal University)

  • Chen Wu

    (Southeast University)

  • Xuejiao Zhu

    (East China Normal University)

  • Yuan He

    (East China Normal University)

  • Fei Mo

    (East China Normal University)

  • Yao Qi

    (East China Normal University)

  • Daqing Jin

    (East China Normal University)

  • Yewei Chen

    (East China Normal University)

  • Xin Zhao

    (Fudan University)

  • Jinzhong Lin

    (Fudan University)

  • Hairong Hu

    (Fudan University)

  • Jia Li

    (Chinese Academy of Sciences)

  • Bing Zhang

    (Shanghai Jiao Tong University)

  • Peng Xie

    (Southeast University)

  • Chengqi Lin

    (Southeast University)

  • Vincent M. Christoffels

    (University of Amsterdam)

  • Yueheng Wu

    (Southern Medical University)

  • Ping Zhu

    (Southern Medical University)

  • Tao P. Zhong

    (East China Normal University)

Abstract

Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in zebrafish hearts or mammalian cardiomyocytes impairs mitochondrial respiration, accompanied by elevated ROS, resulting in cardiomyocyte apoptosis and heart failure. Conversely, Hey2 depletion in adult mouse hearts and zebrafish enhances the expression of mitochondrial oxidation genes and cardiac function. Multifaceted genome-wide analyses reveal that HEY2 enriches at the promoters of genes known to regulate metabolism (including Ppargc1, Esrra and Cpt1) and colocalizes with HDAC1 to effectuate histone deacetylation and transcriptional repression. Consequently, restoration of PPARGC1A/ESRRA in Hey2- overexpressing zebrafish hearts or human cardiomyocyte-like cells rescues deficits in mitochondrial bioenergetics. Knockdown of Hey2 in adult mouse hearts protects against doxorubicin-induced cardiac dysfunction. These studies reveal an evolutionarily conserved HEY2/HDAC1-Ppargc1/Cpt transcriptional module that controls energy metabolism to preserve cardiac function.

Suggested Citation

  • Peilu She & Bangjun Gao & Dongliang Li & Chen Wu & Xuejiao Zhu & Yuan He & Fei Mo & Yao Qi & Daqing Jin & Yewei Chen & Xin Zhao & Jinzhong Lin & Hairong Hu & Jia Li & Bing Zhang & Peng Xie & Chengqi L, 2025. "The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55557-4
    DOI: 10.1038/s41467-024-55557-4
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    References listed on IDEAS

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    1. Jared M. Churko & Priyanka Garg & Barbara Treutlein & Meenakshi Venkatasubramanian & Haodi Wu & Jaecheol Lee & Quinton N. Wessells & Shih-Yu Chen & Wen-Yi Chen & Kashish Chetal & Gary Mantalas & Norma, 2018. "Defining human cardiac transcription factor hierarchies using integrated single-cell heterogeneity analysis," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    2. Xueying Tian & Yan Li & Lingjuan He & Hui Zhang & Xiuzhen Huang & Qiaozhen Liu & Wenjuan Pu & Libo Zhang & Yi Li & Huan Zhao & Zhifu Wang & Jianhong Zhu & Yu Nie & Shengshou Hu & David Sedmera & Tao P, 2017. "Identification of a hybrid myocardial zone in the mammalian heart after birth," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
    3. Ana Paredes & Raquel Justo-Méndez & Daniel Jiménez-Blasco & Vanessa Núñez & Irene Calero & María Villalba-Orero & Andrea Alegre-Martí & Thierry Fischer & Ana Gradillas & Viviane Aparecida Rodrigues Sa, 2023. "γ-Linolenic acid in maternal milk drives cardiac metabolic maturation," Nature, Nature, vol. 618(7964), pages 365-373, June.
    4. Tao P. Zhong & Sarah Childs & James P. Leu & Mark C. Fishman, 2001. "Gridlock signalling pathway fashions the first embryonic artery," Nature, Nature, vol. 414(6860), pages 216-220, November.
    5. Jaecheol Lee & Vittavat Termglinchan & Sebastian Diecke & Ilanit Itzhaki & Chi Keung Lam & Priyanka Garg & Edward Lau & Matthew Greenhaw & Timon Seeger & Haodi Wu & Joe Z. Zhang & Xingqi Chen & Isaac , 2019. "Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy," Nature, Nature, vol. 572(7769), pages 335-340, August.
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