Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathy

Ruya Liu, Jeongkyung Lee, Byung S Kim, Qiongling Wang, Samuel K Buxton, Nikhil Balasubramanyam, Jean J Kim, Jianrong Dong, Aijun Zhang, Shumin Li, Anisha A Gupte, Dale J Hamilton, James F Martin, George G Rodney, Cristian Coarfa, Xander Ht Wehrens, Vijay K Yechoor, Mousumi Moulik

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Heart disease remains the leading cause of death worldwide, highlighting a pressing need to identify novel regulators of cardiomyocyte (CM) function that could be therapeutically targeted. The mammalian Hippo/Tead pathway is critical in embryonic cardiac development and perinatal CM proliferation. However, the requirement of Tead1, the transcriptional effector of this pathway, in the adult heart is unknown. Here, we show that tamoxifen-inducible adult CM-specific Tead1 ablation led to lethal acute-onset dilated cardiomyopathy, associated with impairment in excitation-contraction coupling. Mechanistically, we demonstrate Tead1 is a cell-autonomous, direct transcriptional activator of SERCA2a and SR-associated protein phosphatase 1 regulatory subunit, Inhibitor-1 (I-1). Thus, Tead1 deletion led to a decrease in SERCA2a and I-1 transcripts and protein, with a consequent increase in PP1-activity, resulting in accumulation of dephosphorylated phospholamban (Pln) and decreased SERCA2a activity. Global transcriptomal analysis in Tead1-deleted hearts revealed significant changes in mitochondrial and sarcomere-related pathways. Additional studies demonstrated there was a trend for correlation between protein levels of TEAD1 and I-1, and phosphorylation of PLN, in human nonfailing and failing hearts. Furthermore, TEAD1 activity was required to maintain PLN phosphorylation and expression of SERCA2a and I-1 in human induced pluripotent stem cell-derived (iPS-derived) CMs. To our knowledge, taken together, this demonstrates a nonredundant, novel role of Tead1 in maintaining normal adult heart function.

Original languageEnglish (US)
JournalJCI insight
Volume2
Issue number17
Early online dateSep 7 2017
DOIs
StatePublished - Sep 7 2017

Keywords

  • Calcium
  • Cardiology
  • Cell Biology
  • Heart failure
  • Transcription

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    Liu, R., Lee, J., Kim, B. S., Wang, Q., Buxton, S. K., Balasubramanyam, N., Kim, J. J., Dong, J., Zhang, A., Li, S., Gupte, A. A., Hamilton, D. J., Martin, J. F., Rodney, G. G., Coarfa, C., Wehrens, X. H., Yechoor, V. K., & Moulik, M. (2017). Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathy. JCI insight, 2(17). https://doi.org/10.1172/jci.insight.93343