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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Bywater, Megan 
Burkhart, Deborah 
Straube, Jasmin 
Sabo, Arianna 

Abstract

It is unclear why some tissues are refractory to the mitogenic effects of the oncogene Myc. Here we show, 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 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.

Description

Keywords

Animals, Cell Proliferation, Chromatin, Cyclin T, Mice, Myocardium, Myocytes, Cardiac, Organ Specificity, Phosphorylation, Positive Transcriptional Elongation Factor B, Protein Binding, Proto-Oncogene Proteins c-myc, Transcription, Genetic, Transcriptional Activation

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

Publisher

Springer Nature
Sponsorship
Cancer Research Uk (None)
Cancer Research UK (19013)
Cancer Research UK (22585)