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Targeting transcription in heart failure via CDK7/12/13 inhibition

Author

Listed:
  • Austin Hsu

    (Gladstone Institutes
    Biomedical Sciences Graduate Program)

  • Qiming Duan

    (Gladstone Institutes)

  • Daniel S. Day

    (Whitehead Institute for Biomedical Research)

  • Xin Luo

    (Amgen Research)

  • Sarah McMahon

    (Gladstone Institutes
    Biomedical Sciences Graduate Program)

  • Yu Huang

    (Gladstone Institutes)

  • Zachary B. Feldman

    (Vanderbilt University Medical Center)

  • Zhen Jiang

    (Gladstone Institutes
    Amgen Research)

  • Tinghu Zhang

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Yanke Liang

    (Harvard Medical School
    Massachusetts Institute of Technology)

  • Michael Alexanian

    (Gladstone Institutes)

  • Arun Padmanabhan

    (Gladstone Institutes
    UCSF)

  • Jonathan D. Brown

    (Vanderbilt University Medical Center)

  • Charles Y. Lin

    (Baylor College of Medicine)

  • Nathanael S. Gray

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Stanford University)

  • Richard A. Young

    (Whitehead Institute for Biomedical Research
    Massachusetts Institute of Technology)

  • Benoit G. Bruneau

    (Gladstone Institutes
    UCSF)

  • Saptarsi M. Haldar

    (Gladstone Institutes
    Amgen Research
    UCSF)

Abstract

Heart failure with reduced ejection fraction (HFrEF) is associated with high mortality, highlighting an urgent need for new therapeutic strategies. As stress-activated cardiac signaling cascades converge on the nucleus to drive maladaptive gene programs, interdicting pathological transcription is a conceptually attractive approach for HFrEF therapy. Here, we demonstrate that CDK7/12/13 are critical regulators of transcription activation in the heart that can be pharmacologically inhibited to improve HFrEF. CDK7/12/13 inhibition using the first-in-class inhibitor THZ1 or RNAi blocks stress-induced transcription and pathologic hypertrophy in cultured rodent cardiomyocytes. THZ1 potently attenuates adverse cardiac remodeling and HFrEF pathogenesis in mice and blocks cardinal features of disease in human iPSC-derived cardiomyocytes. THZ1 suppresses Pol II enrichment at stress-transactivated cardiac genes and inhibits a specific pathologic gene program in the failing mouse heart. These data identify CDK7/12/13 as druggable regulators of cardiac gene transactivation during disease-related stress, suggesting that HFrEF features a critical dependency on transcription that can be therapeutically exploited.

Suggested Citation

  • Austin Hsu & Qiming Duan & Daniel S. Day & Xin Luo & Sarah McMahon & Yu Huang & Zachary B. Feldman & Zhen Jiang & Tinghu Zhang & Yanke Liang & Michael Alexanian & Arun Padmanabhan & Jonathan D. Brown , 2022. "Targeting transcription in heart failure via CDK7/12/13 inhibition," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31541-8
    DOI: 10.1038/s41467-022-31541-8
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    References listed on IDEAS

    as
    1. Nadine Czudnochowski & Christian A. Bösken & Matthias Geyer, 2012. "Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition," Nature Communications, Nature, vol. 3(1), pages 1-12, January.
    2. Michael Alexanian & Pawel F. Przytycki & Rudi Micheletti & Arun Padmanabhan & Lin Ye & Joshua G. Travers & Barbara Gonzalez-Teran & Ana Catarina Silva & Qiming Duan & Sanjeev S. Ranade & Franco Felix , 2021. "A transcriptional switch governs fibroblast activation in heart disease," Nature, Nature, vol. 595(7867), pages 438-443, July.
    3. Nicholas Kwiatkowski & Tinghu Zhang & Peter B. Rahl & Brian J. Abraham & Jessica Reddy & Scott B. Ficarro & Anahita Dastur & Arnaud Amzallag & Sridhar Ramaswamy & Bethany Tesar & Catherine E. Jenkins , 2014. "Targeting transcription regulation in cancer with a covalent CDK7 inhibitor," Nature, Nature, vol. 511(7511), pages 616-620, July.
    4. Florencia Cayrol & Pannee Praditsuktavorn & Tharu M. Fernando & Nicholas Kwiatkowski & Rosella Marullo & M. Nieves Calvo-Vidal & Jude Phillip & Benet Pera & Shao Ning Yang & Kaipol Takpradit & Lidia R, 2017. "THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors," Nature Communications, Nature, vol. 8(1), pages 1-12, April.
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