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

Author:

Bywater Megan J.,Burkhart Deborah L.ORCID,Straube Jasmin,Sabò AriannaORCID,Pendino VeraORCID,Hudson James E.,Quaife-Ryan Gregory A.ORCID,Porrello Enzo R.,Rae James,Parton Robert G.ORCID,Kress Theresia R.,Amati BrunoORCID,Littlewood Trevor D.ORCID,Evan Gerard I.ORCID,Wilson Catherine H.ORCID

Abstract

AbstractIt 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.

Funder

Cancer Research UK

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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