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.
Highlights
After birth, cardiomyocytes (CM) acquire numerous adaptations in order to efficiently pump blood throughout an animal’s lifespan
We identify a hierarchy of maturation processes, in which sarcomere maturation was required for morphological maturation but mitochondrial biogenesis was not
Reasoning that CM maturation may be regulated by factors that regulate CM differentiation, we studied nine transcriptional regulators of CM differentiation (Gata[4], Gata[6], Mef2a, Mef2c, Tead[1], serum response factor (Srf), Tbx[5], Nkx2.5, and Tead1) as candidate maturation factors (Supplementary Fig. 1b)
Summary
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. We perform a CRISPR/Cas[9] screen in mice and identify serum response factor (SRF) as a key regulator of CM maturation. 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. Studies in mice with organ-wide gene modifications have been confounded by secondary effects, such as the de-maturation-like phenotypes of heart failure[6]. We perform a CASAAV-based screen and identified serum response factor (Srf) as a key regulator of CM maturation. We identify a hierarchy of maturation processes, in which sarcomere maturation was required for morphological maturation but mitochondrial biogenesis was not
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