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

Nature Communications
Yuxuan GuoWilliam T Pu

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.

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Citations

Dec 21, 2018·The Journal of Physiology·Suraj Kannan, Chulan Kwon
Apr 10, 2020·Circulation Research·Yuxuan Guo, William T Pu
Jul 15, 2020·Biophysics Reviews·Fujian Lu, William T Pu
Jun 6, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Ruya LiuMousumi Moulik
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Oct 25, 2020·Cardiovascular Toxicology·Peng YueYifei Li
Dec 2, 2020·International Journal of Molecular Sciences·Junjun LiYoshiki Sawa
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Dec 29, 2020·Proceedings of the National Academy of Sciences of the United States of America·Yuxuan GuoWilliam T Pu
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Mar 14, 2021·Nature Communications·Sean A MurphyChulan Kwon
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May 2, 2021·Seminars in Cell & Developmental Biology·Emmanouil Tampakakis, Ahmed I Mahmoud
May 7, 2021·Seminars in Cell & Developmental Biology·Sean A MurphyChulan Kwon
Mar 8, 2021·Clinical and Experimental Pediatrics·Heeyoung SeokDa-Zhi Wang
Jul 31, 2021·Korean Circulation Journal·Heeyoung Seok, Jin-Hee Oh
Oct 30, 2021·International Journal of Stem Cells·Yingnan LiaoYan Wang

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Methods Mentioned

BETA
RNA-seq
flow cytometry
FACS
electron microscopy
pull-down
immunoprecipitation
bioChIP-Seq
ChIP-seq
transfection
dissection

Software Mentioned

GPP Web
FeatureCounts
EM
FACS
DESeq2 enrichment analysis ( GSEA )
DESeq2
Bowtie 2
Integrated Genome Viewer
Vevostrain
GSEA

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