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Hierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor

Author

Listed:
  • Yuxuan Guo

    (Boston Children’s Hospital)

  • Blake D. Jardin

    (Boston Children’s Hospital
    Boston University)

  • Pingzhu Zhou

    (Boston Children’s Hospital)

  • Isha Sethi

    (Dana-Farber Cancer Institute)

  • Brynn N. Akerberg

    (Boston Children’s Hospital)

  • Christopher N Toepfer

    (Harvard Medical School
    University of Oxford)

  • Yulan Ai

    (Boston Children’s Hospital)

  • Yifei Li

    (Boston Children’s Hospital
    Sichuan University)

  • Qing Ma

    (Boston Children’s Hospital)

  • Silvia Guatimosim

    (Universidade Federal de Minas Gerais)

  • Yongwu Hu

    (Boston Children’s Hospital
    Wenzhou Medical University, School of Life Sciences)

  • Grigor Varuzhanyan

    (California Institute of Technology)

  • Nathan J. VanDusen

    (Boston Children’s Hospital)

  • Donghui Zhang

    (Boston Children’s Hospital
    Hubei University)

  • David C. Chan

    (California Institute of Technology)

  • Guo-Cheng Yuan

    (Dana-Farber Cancer Institute)

  • Christine E. Seidman

    (Harvard Medical School
    Brigham and Women’s Hospital
    Howard Hughes Medical Institute)

  • Jonathan G. Seidman

    (Harvard Medical School)

  • William T. Pu

    (Boston Children’s Hospital
    Harvard Stem Cell Institute)

Abstract

After birth, cardiomyocytes (CM) acquire numerous adaptations in order to efficiently pump blood throughout an animal’s lifespan. How this maturation process is regulated and coordinated is poorly understood. Here, we perform a CRISPR/Cas9 screen in mice and identify serum response factor (SRF) as a key regulator of CM maturation. Mosaic SRF depletion in neonatal CMs disrupts many aspects of their maturation, including sarcomere expansion, mitochondrial biogenesis, transverse-tubule formation, and cellular hypertrophy. Maintenance of maturity in adult CMs is less dependent on SRF. This stage-specific activity is associated with developmentally regulated SRF chromatin occupancy and transcriptional regulation. SRF directly activates genes that regulate sarcomere assembly and mitochondrial dynamics. Perturbation of sarcomere assembly but not mitochondrial dynamics recapitulates SRF knockout phenotypes. SRF overexpression also perturbs CM maturation. Together, these data indicate that carefully balanced SRF activity is essential to promote CM maturation through a hierarchy of cellular processes orchestrated by sarcomere assembly.

Suggested Citation

  • Yuxuan Guo & Blake D. Jardin & Pingzhu Zhou & Isha Sethi & Brynn N. Akerberg & Christopher N Toepfer & Yulan Ai & Yifei Li & Qing Ma & Silvia Guatimosim & Yongwu Hu & Grigor Varuzhanyan & Nathan J. Va, 2018. "Hierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06347-2
    DOI: 10.1038/s41467-018-06347-2
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    Cited by:

    1. Caroline Dour & Maria Chatzifrangkeskou & Coline Macquart & Maria M. Magiera & Cécile Peccate & Charlène Jouve & Laura Virtanen & Tiina Heliö & Katriina Aalto-Setälä & Silvia Crasto & Bruno Cadot & Dé, 2022. "Actin-microtubule cytoskeletal interplay mediated by MRTF-A/SRF signaling promotes dilated cardiomyopathy caused by LMNA mutations," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

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