PGC1/PPAR drive cardiomyocyte maturation at single cell level via YAP1 and SF3B2

Sean A. Murphy, Matthew Miyamoto, Anaïs Kervadec, Suraj Kannan, Emmanouil Tampakakis, Sandeep Kambhampati, Brian Leei Lin, Sam Paek, Peter Andersen, Dong-Ik Lee, Renjun Zhu, Steven S. An, David A. Kass, Hideki Uosaki, Alexandre R. Colas and Chulan Kwon ()
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Sean A. Murphy: Johns Hopkins University School of Medicine
Matthew Miyamoto: Johns Hopkins University School of Medicine
Anaïs Kervadec: Sanford Burnham Prebys Medical Discovery Institute
Suraj Kannan: Johns Hopkins University School of Medicine
Emmanouil Tampakakis: Johns Hopkins University School of Medicine
Sandeep Kambhampati: Johns Hopkins University School of Medicine
Brian Leei Lin: Johns Hopkins University School of Medicine
Sam Paek: Rutgers Institute for Translational Medicine and Science
Peter Andersen: Johns Hopkins University School of Medicine
Dong-Ik Lee: Johns Hopkins University School of Medicine
Renjun Zhu: Johns Hopkins University School of Medicine
Steven S. An: Rutgers Institute for Translational Medicine and Science
David A. Kass: Johns Hopkins University School of Medicine
Hideki Uosaki: Johns Hopkins University School of Medicine
Alexandre R. Colas: Sanford Burnham Prebys Medical Discovery Institute
Chulan Kwon: Johns Hopkins University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Cardiomyocytes undergo significant structural and functional changes after birth, and these fundamental processes are essential for the heart to pump blood to the growing body. However, due to the challenges of isolating single postnatal/adult myocytes, how individual newborn cardiomyocytes acquire multiple aspects of the mature phenotype remains poorly understood. Here we implement large-particle sorting and analyze single myocytes from neonatal to adult hearts. Early myocytes exhibit wide-ranging transcriptomic and size heterogeneity that is maintained until adulthood with a continuous transcriptomic shift. Gene regulatory network analysis followed by mosaic gene deletion reveals that peroxisome proliferator-activated receptor coactivator-1 signaling, which is active in vivo but inactive in pluripotent stem cell-derived cardiomyocytes, mediates the shift. This signaling simultaneously regulates key aspects of cardiomyocyte maturation through previously unrecognized proteins, including YAP1 and SF3B2. Our study provides a single-cell roadmap of heterogeneous transitions coupled to cellular features and identifies a multifaceted regulator controlling cardiomyocyte maturation.

Date: 2021
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DOI: 10.1038/s41467-021-21957-z

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