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

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, Bruno Amati, Trevor D. Littlewood, Gerard I. Evan, Catherine H. Wilson

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number1827
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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