机构：[1]Department of Cardiology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA[2]Department of Biology, Boston University, 5Cummington Mall, Boston, MA 02215, USA[3]Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue,Boston, MA 02215, USA[4]Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA[5]Radcliffe Department ofMedicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK[6]Key Laboratory of Birth Defects andRelated Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, 610041 Chengdu,Sichuan, China[7]Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, AvA.ntônio Carlos 6627,Belo Horizonte, MG CEP: 31270-901, Brazil[8]Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Boulevard,MC 114-96, Pasadena, CA 91125, USA[9]Division of Cardiovascular Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA[10]Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA[11]Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge,MA 02138, USA[12]Present address: Wenzhou Medical University, School of Life Sciences, Wenzhou, China[13]Present address: Hubei CollaborativeInnovation Center for Green Transformation of Bio-resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University,430062 Wuhan, China
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.
基金：
This work was supported by funding from
NIH NHLBI (2UM1 HL098166 and U01HL131003), the American Heart Association
(AHA) (17IRG33410894), and charitable support from the Boston Children’s
Hospital Department of Cardiology. S.G. was a recipient of a Coordenação de Aperfeiçoamento
de Pessoal de Nível Superior fellowship and funded by Conselho Nacional de
Desenvolvimento Científico e Tecnológico and Fundação de Amparo a Pesquisa do
Estado de Minas Gerais. C.N.T. is a recipient of Sir Henry Wellcome Postdoctoral
Fellowship 206466/Z/17/Z. Y.G. is a recipient of AHA postdoctoral fellowship
18POST33960037.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2018]版：
大类|2 区综合性期刊
小类|2 区综合性期刊
最新[2025]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
第一作者：
第一作者机构：[1]Department of Cardiology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA
通讯作者：
通讯机构：[1]Department of Cardiology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA[11]Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge,MA 02138, USA
推荐引用方式(GB/T 7714)：
Yuxuan Guo,Blake D. Jardin,Pingzhu Zhou,et al.Hierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor.[J].Nature communications.2018,9(1):3837.doi:10.1038/s41467-018-06347-2.
APA：
Yuxuan Guo,Blake D. Jardin,Pingzhu Zhou,Isha Sethi,Brynn N. Akerberg...&William T. Pu.(2018).Hierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor..Nature communications,9,(1)
MLA：
Yuxuan Guo,et al."Hierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor.".Nature communications 9..1(2018):3837
综合性期刊