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

Research output: Contribution to journalArticle

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

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

PMID: 28878117

PMCID: PMC5621883

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Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathy. / Liu, Ruya; Lee, Jeongkyung; Kim, Byung S; Wang, Qiongling; Buxton, Samuel K; Balasubramanyam, Nikhil; Kim, Jean J; Dong, Jianrong; Zhang, Aijun; Li, Shumin; Gupte, Anisha A; Hamilton, Dale J; Martin, James F; Rodney, George G; Coarfa, Cristian; Wehrens, Xander Ht; Yechoor, Vijay K; Moulik, Mousumi.

In: JCI Insight, Vol. 2, No. 17, 07.09.2017.

Research output: Contribution to journalArticle

Harvard

Liu, R, Lee, J, Kim, BS, Wang, Q, Buxton, SK, Balasubramanyam, N, Kim, JJ, Dong, J, Zhang, A, Li, S, Gupte, AA, Hamilton, DJ, Martin, JF, Rodney, GG, Coarfa, C, Wehrens, XH, Yechoor, VK & Moulik, M 2017, 'Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathy' JCI Insight, vol. 2, no. 17. https://doi.org/10.1172/jci.insight.93343

APA

Liu, R., Lee, J., Kim, B. S., Wang, Q., Buxton, S. K., Balasubramanyam, N., ... 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

Vancouver

Liu R, Lee J, Kim BS, Wang Q, Buxton SK, Balasubramanyam N et al. Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathy. JCI Insight. 2017 Sep 7;2(17). https://doi.org/10.1172/jci.insight.93343

Author

Liu, Ruya ; Lee, Jeongkyung ; Kim, Byung S ; Wang, Qiongling ; Buxton, Samuel K ; Balasubramanyam, Nikhil ; Kim, Jean J ; Dong, Jianrong ; Zhang, Aijun ; Li, Shumin ; Gupte, Anisha A ; Hamilton, Dale J ; Martin, James F ; Rodney, George G ; Coarfa, Cristian ; Wehrens, Xander Ht ; Yechoor, Vijay K ; Moulik, Mousumi. / Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathy. In: JCI Insight. 2017 ; Vol. 2, No. 17.

BibTeX

@article{29ec521eb3c647a7a0c94fd3eeb731ca,
title = "Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathy",
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.",
keywords = "Calcium, Cardiology, Cell Biology, Heart failure, Transcription",
author = "Ruya Liu and Jeongkyung Lee and Kim, {Byung S} and Qiongling Wang and Buxton, {Samuel K} and Nikhil Balasubramanyam and Kim, {Jean J} and Jianrong Dong and Aijun Zhang and Shumin Li and Gupte, {Anisha A} and Hamilton, {Dale J} and Martin, {James F} and Rodney, {George G} and Cristian Coarfa and Wehrens, {Xander Ht} and Yechoor, {Vijay K} and Mousumi Moulik",
year = "2017",
month = "9",
day = "7",
doi = "10.1172/jci.insight.93343",
language = "English (US)",
volume = "2",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "17",

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RIS

TY - JOUR

T1 - Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathy

AU - Liu, Ruya

AU - Lee, Jeongkyung

AU - Kim, Byung S

AU - Wang, Qiongling

AU - Buxton, Samuel K

AU - Balasubramanyam, Nikhil

AU - Kim, Jean J

AU - Dong, Jianrong

AU - Zhang, Aijun

AU - Li, Shumin

AU - Gupte, Anisha A

AU - Hamilton, Dale J

AU - Martin, James F

AU - Rodney, George G

AU - Coarfa, Cristian

AU - Wehrens, Xander Ht

AU - Yechoor, Vijay K

AU - Moulik, Mousumi

PY - 2017/9/7

Y1 - 2017/9/7

N2 - 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.

AB - 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.

KW - Calcium

KW - Cardiology

KW - Cell Biology

KW - Heart failure

KW - Transcription

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U2 - 10.1172/jci.insight.93343

DO - 10.1172/jci.insight.93343

M3 - Article

VL - 2

JO - JCI Insight

T2 - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 17

ER -

ID: 42458248