TY - JOUR
T1 - Hierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor
AU - Guo, Yuxuan
AU - Jardin, Blake D.
AU - Zhou, Pingzhu
AU - Sethi, Isha
AU - Akerberg, Brynn N.
AU - Toepfer, Christopher N.
AU - Ai, Yulan
AU - Li, Yifei
AU - Ma, Qing
AU - Guatimosim, Silvia
AU - Hu, Yongwu
AU - Varuzhanyan, Grigor
AU - VanDusen, Nathan J.
AU - Zhang, Donghui
AU - Chan, David C.
AU - Yuan, Guo Cheng
AU - Seidman, Christine E.
AU - Seidman, Jonathan G.
AU - Pu, William T.
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85053722487
U2 - 10.1038/s41467-018-06347-2
DO - 10.1038/s41467-018-06347-2
M3 - Article
C2 - 30242271
AN - SCOPUS:85053722487
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3837
ER -