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.

Details

Title
Hierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor
Author
Guo, Yuxuan 1   VIAFID ORCID Logo  ; Jardin, Blake D 2   VIAFID ORCID Logo  ; Zhou, Pingzhu 1 ; Sethi, Isha 3 ; Akerberg, Brynn N 1 ; Toepfer, Christopher N 4   VIAFID ORCID Logo  ; Ai, Yulan 1 ; Li, Yifei 5   VIAFID ORCID Logo  ; Ma, Qing 1 ; Guatimosim, Silvia 6 ; Hu, Yongwu 7 ; Varuzhanyan, Grigor 8   VIAFID ORCID Logo  ; VanDusen, Nathan J 1 ; Zhang, Donghui 9 ; Chan, David C 8 ; Guo-Cheng, Yuan 3   VIAFID ORCID Logo  ; Seidman, Christine E 10   VIAFID ORCID Logo  ; Seidman, Jonathan G 11 ; Pu, William T 12   VIAFID ORCID Logo 

 Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA 
 Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA; Department of Biology, Boston University, Boston, MA, USA 
 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA 
 Department of Genetics, Harvard Medical School, Boston, MA, USA; Radcliffe Department of Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK 
 Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA; Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China 
 Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil 
 Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA; Wenzhou Medical University, School of Life Sciences, Wenzhou, China 
 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA 
 Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA; Hubei Collaborative Innovation Center for Green Transformation of Bio-resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China 
10  Department of Genetics, Harvard Medical School, Boston, MA, USA; Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA 
11  Department of Genetics, Harvard Medical School, Boston, MA, USA 
12  Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA 
Pages
1-16
Publication year
2018
Publication date
Sep 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2110819544
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.