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

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. VanDusen, Donghui Zhang, David C. Chan, Guo-Cheng Yuan, Christine E. Seidman, Jonathan G. Seidman and William T. Pu ()
Additional contact information
Yuxuan Guo: Boston Children’s Hospital
Blake D. Jardin: Boston Children’s Hospital
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
Yulan Ai: Boston Children’s Hospital
Yifei Li: Boston Children’s Hospital
Qing Ma: Boston Children’s Hospital
Silvia Guatimosim: Universidade Federal de Minas Gerais
Yongwu Hu: Boston Children’s Hospital
Grigor Varuzhanyan: California Institute of Technology
Nathan J. VanDusen: Boston Children’s Hospital
Donghui Zhang: Boston Children’s Hospital
David C. Chan: California Institute of Technology
Guo-Cheng Yuan: Dana-Farber Cancer Institute
Christine E. Seidman: Harvard Medical School
Jonathan G. Seidman: Harvard Medical School
William T. Pu: Boston Children’s Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06347-2

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