RT Journal Article
SR Electronic
T1 PGC1/PPAR Drive Cardiomyocyte Maturation through Regulation of Yap1 and SF3B2
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.02.06.937797
DO 10.1101/2020.02.06.937797
A1 Sean Murphy
A1 Matthew Miyamoto
A1 Anais Kervadec
A1 Suraj Kannan
A1 Emmanouil Tampakakis
A1 Sandeep Kambhampati
A1 Brian Leei Lin
A1 Sam Paek
A1 Peter Andersen
A1 Dong-Ik Lee
A1 Renjun Zhu
A1 Steven S. An
A1 David A. Kass
A1 Hideki Uosaki
A1 Alexandre R. Colas
A1 Chulan Kwon
YR 2020
UL http://biorxiv.org/content/early/2020/02/07/2020.02.06.937797.abstract
AB Cardiomyocytes undergo significant levels of structural and functional changes after birth—fundamental processes essential for the heart to produce the volume and contractility to pump blood to the growing body. However, due to the challenges in isolating single postnatal/adult myocytes, how individual newborn cardiomyocytes acquire multiple aspects of mature phenotypes remains poorly understood. Here we implemented large-particle sorting and analyzed single myocytes from neonatal to adult hearts. Early myocytes exhibited a wide-ranging transcriptomic and size heterogeneity, maintained until adulthood with a continuous transcriptomic shift. Gene regulatory network analysis followed by mosaic gene deletion revealed that peroxisome proliferator-activated receptor coactivator-1 signaling—activated in vivo but inactive in pluripotent stem cell-derived cardiomyocytes—mediates the shift. The signaling regulated key aspects of cardiomyocyte maturation simultaneously through previously unrecognized regulators, including Yap1 and SF3B2. Our study provides a single-cell roadmap of heterogeneous transitions coupled to cellular features and unveils a multifaceted regulator controlling cardiomyocyte maturation.Significance Statement How the individual single myocytes achieve full maturity remains a ‘black box’, largely due to the challenges with the isolation of single mature myocytes. Understanding this process is particularly important as the immaturity and early developmental arrest of pluripotent stem cell-derived myocytes has emerged a major concern in the field. Here we present the first study of high-quality single-cell transcriptomic analysis of cardiac muscle cells from neonatal to adult hearts. We identify a central transcription factor and its novel targets that control key aspects of myocyte maturation, including cellular hypertrophy, contractility, and mitochondrial activity.