IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-31541-8.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-31541-8
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-31541-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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. 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.
    3. 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.
    4. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Fabian Peisker & Maurice Halder & James Nagai & Susanne Ziegler & Nadine Kaesler & Konrad Hoeft & Ronghui Li & Eric M. J. Bindels & Christoph Kuppe & Julia Moellmann & Michael Lehrke & Christian Stopp, 2022. "Mapping the cardiac vascular niche in heart failure," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    2. Robert Düster & Kanchan Anand & Sophie C. Binder & Maximilian Schmitz & Karl Gatterdam & Robert P. Fisher & Matthias Geyer, 2024. "Structural basis of Cdk7 activation by dual T-loop phosphorylation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Jieqiong Zhang & Zhenhua Hu & Hwa Hwa Chung & Yun Tian & Kah Weng Lau & Zheng Ser & Yan Ting Lim & Radoslaw M. Sobota & Hwei Fen Leong & Benjamin Jieming Chen & Clarisse Jingyi Yeo & Shawn Ying Xuan T, 2023. "Dependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    4. Ines H. Kaltheuner & Kanchan Anand & Jonas Moecking & Robert Düster & Jinhua Wang & Nathanael S. Gray & Matthias Geyer, 2021. "Abemaciclib is a potent inhibitor of DYRK1A and HIP kinases involved in transcriptional regulation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    5. Anniina Vihervaara & Philip Versluis & Samu V. Himanen & John T. Lis, 2023. "PRO-IP-seq tracks molecular modifications of engaged Pol II complexes at nucleotide resolution," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    6. Tengfei Wang & Shuxiang Shi & Yuanyuan Shi & Peipei Jiang & Ganlu Hu & Qinying Ye & Zhan Shi & Kexin Yu & Chenguang Wang & Guoping Fan & Suwen Zhao & Hanhui Ma & Alex C. Y. Chang & Zhi Li & Qian Bian , 2023. "Chemical-induced phase transition and global conformational reorganization of chromatin," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    7. Victoria I. Cushing & Adrian F. Koh & Junjie Feng & Kaste Jurgaityte & Alexander Bondke & Sebastian H. B. Kroll & Marion Barbazanges & Bodo Scheiper & Ash K. Bahl & Anthony G. M. Barrett & Simak Ali &, 2024. "High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    8. Ian Fernandes & Shunsuke Funakoshi & Homaira Hamidzada & Slava Epelman & Gordon Keller, 2023. "Modeling cardiac fibroblast heterogeneity from human pluripotent stem cell-derived epicardial cells," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    9. Thibault Houles & Geneviève Lavoie & Sami Nourreddine & Winnie Cheung & Éric Vaillancourt-Jean & Célia M. Guérin & Mathieu Bouttier & Benoit Grondin & Sichun Lin & Marc K. Saba-El-Leil & Stephane Ange, 2022. "CDK12 is hyperactivated and a synthetic-lethal target in BRAF-mutated melanoma," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Jayden Sterling & Jennifer R. Baker & Adam McCluskey & Lenka Munoz, 2023. "Systematic literature review reveals suboptimal use of chemical probes in cell-based biomedical research," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    11. Barbara Steurer & Roel C. Janssens & Marit E. Geijer & Fernando Aprile-Garcia & Bart Geverts & Arjan F. Theil & Barbara Hummel & Martin E. Royen & Bastiaan Evers & René Bernards & Adriaan B. Houtsmull, 2022. "DNA damage-induced transcription stress triggers the genome-wide degradation of promoter-bound Pol II," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31541-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.