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Reactivation of Myc transcription in the mouse heart unlocks its proliferative capacity

Author

Listed:
  • Megan J. Bywater

    (University of Cambridge
    QIMR Berghofer Medical Research Institute)

  • Deborah L. Burkhart

    (University of Cambridge)

  • Jasmin Straube

    (QIMR Berghofer Medical Research Institute)

  • Arianna Sabò

    (European Institute of Oncology (IEO) - IRCCS)

  • Vera Pendino

    (Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT))

  • James E. Hudson

    (QIMR Berghofer Medical Research Institute)

  • Gregory A. Quaife-Ryan

    (QIMR Berghofer Medical Research Institute)

  • Enzo R. Porrello

    (The Royal Children’s Hospital
    The University of Melbourne)

  • James Rae

    (The University of Queensland)

  • Robert G. Parton

    (The University of Queensland
    The University of Queensland)

  • Theresia R. Kress

    (Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT))

  • Bruno Amati

    (European Institute of Oncology (IEO) - IRCCS)

  • Trevor D. Littlewood

    (University of Cambridge)

  • Gerard I. Evan

    (University of Cambridge)

  • Catherine H. Wilson

    (University of Cambridge
    University of Cambridge)

Abstract

It is unclear why some tissues are refractory to the mitogenic effects of the oncogene Myc. Here we show that Myc activation induces rapid transcriptional responses followed by proliferation in some, but not all, organs. Despite such disparities in proliferative response, Myc is bound to DNA at open elements in responsive (liver) and non-responsive (heart) tissues, but fails to induce a robust transcriptional and proliferative response in the heart. Using heart as an exemplar of a non-responsive tissue, we show that Myc-driven transcription is re-engaged in mature cardiomyocytes by elevating levels of the positive transcription elongation factor (P-TEFb), instating a large proliferative response. Hence, P-TEFb activity is a key limiting determinant of whether the heart is permissive for Myc transcriptional activation. These data provide a greater understanding of how Myc transcriptional activity is determined and indicate modification of P-TEFb levels could be utilised to drive regeneration of adult cardiomyocytes for the treatment of heart myopathies.

Suggested Citation

  • Megan J. Bywater & Deborah L. Burkhart & Jasmin Straube & Arianna Sabò & Vera Pendino & James E. Hudson & Gregory A. Quaife-Ryan & Enzo R. Porrello & James Rae & Robert G. Parton & Theresia R. Kress &, 2020. "Reactivation of Myc transcription in the mouse heart unlocks its proliferative capacity," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15552-x
    DOI: 10.1038/s41467-020-15552-x
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    Cited by:

    1. Nicole M. Sodir & Luca Pellegrinet & Roderik M. Kortlever & Tania Campos & Yong-Won Kwon & Shinseog Kim & Daniel Garcia & Alessandra Perfetto & Panayiotis Anastasiou & Lamorna Brown Swigart & Mark J. , 2022. "Reversible Myc hypomorphism identifies a key Myc-dependency in early cancer evolution," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Rebecca J. Austin & Jasmin Straube & Rohit Halder & Yashaswini Janardhanan & Claudia Bruedigam & Matthew Witkowski & Leanne Cooper & Amy Porter & Matthias Braun & Fernando Souza-Fonseca-Guimaraes & Si, 2023. "Oncogenic drivers dictate immune control of acute myeloid leukemia," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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