Hierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor
Year: 2018
Type: article
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.
Source: Nature Communications
Authors: 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, William T. Pu
Institutions: Boston Children's Hospital, Boston University, Dana-Farber Cancer Institute, Centre for Human Genetics, Harvard University, University of Oxford, Sichuan University, West China Second University Hospital of Sichuan University, Universidade Federal de Minas Gerais, Wenzhou Medical University, California Institute of Technology, Hubei University, Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Stem Cell Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Health and Human Services, American Heart Association, Boston Children's Hospital, Dana-Farber Cancer Institute, Wellcome Trust, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Conselho Nacional de Desenvolvimento Científico e Tecnológico, National Institutes of Health, National Heart, Lung, and Blood Institute
Awards: Determine the role of serum response factor signaling in cardiomyocyte maturation, Regulation of Cardiac Development in Health and Disease, Regulation of Cardiomyocyte Maturation, G5639575814, Forward genetic screen to discover regulators of mammalian cardiomyocyte maturation, Mechanisms by which missense variants in myosin and myosin binding protein C alter cellular contractility in genetic cardiomyopathies., Administrative Coordinating Center: Bench to Bassinet Program, G8391622861
OpenAlex ID: W2889940320