TY - JOUR
T1 - Reactivation of Myc transcription in the mouse heart unlocks its proliferative capacity
AU - Bywater, Megan J.
AU - Burkhart, Deborah L.
AU - Straube, Jasmin
AU - Sabò, Arianna
AU - Pendino, Vera
AU - Hudson, James E.
AU - Quaife-Ryan, Gregory A.
AU - Porrello, Enzo R.
AU - Rae, James
AU - Parton, Robert G.
AU - Kress, Theresia R.
AU - Amati, Bruno
AU - Littlewood, Trevor D.
AU - Evan, Gerard I.
AU - Wilson, Catherine H.
N1 - Funding Information:
The authors thank the support staff in the Cambridge University Biomedical Services at the Gurdon Institute and CRUK Cambridge Institute. We would like to thank AstraZeneca and, specifically, Lisa Drew and Justin Cidado for AZ5576 supply and guidance. We would like to thank Steven Lane for laboratory support and critical advice on the manuscript. The authors acknowledge the use of the Microscopy Australia Research Facility at the Center for Microscopy and Microanalysis at The University of Queensland. We would like to thank Charles Ferguson, Robyn Webb and Marcel Sayre (CMM, UQ), for assistance with electron microscopy. We also thank Roger Foo and Peter Li from the National University Heart Centre, Singapore for their technical advice on the isolation and infection of adult cardiomyocytes. This work was primarily supported by CRUK (Programme Grant A19013 to GIE). M.J.B. was funded by an EMBO long-term fellowship and an Australian NHMRC Early Career Fellowship (APP1072477). This work was supported by funding from the European Research Council (grant agreement no. 268671-MYCNEXT), the Italian Health Ministry (RF-2011-02346976) and the Italian Association for Cancer Research (AIRC, IG 2015-16768 and IG 2018-21594) to B.A., and from Worldwide Cancer Research (15-1260) to A.S. This work was also supported by the National Health and Medical Research Council of Australia (grants APP1140064 and APP1150083 and fellowship APP1156489 to R.G.P.). R.G.P. is supported by the Australian Research Council (ARC) Centre of Excellence in Convergent Bio-Nano Science and Technology.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-15552-x
DO - 10.1038/s41467-020-15552-x
M3 - Article
C2 - 32286286
AN - SCOPUS:85083417672
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1827
ER -