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

Autor: Bywater MJ; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK.; QIMR Berghofer Medical Research Institute, Herston, QLD, Australia., Burkhart DL; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK., Straube J; QIMR Berghofer Medical Research Institute, Herston, QLD, Australia., Sabò A; Department of Experimental Oncology, European Institute of Oncology (IEO) - IRCCS, Via Adamello 16, 20139, Milan, Italy., Pendino V; Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Via Adamello 16, 20139, Milan, Italy., Hudson JE; QIMR Berghofer Medical Research Institute, Herston, QLD, Australia., Quaife-Ryan GA; QIMR Berghofer Medical Research Institute, Herston, QLD, Australia., Porrello ER; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, 3052, Australia.; Department of Physiology, School of Biomedical Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia., Rae J; Institute for Molecular Bioscience, The University of Queensland, St Lucia, 4072, QLD, Australia., Parton RG; Institute for Molecular Bioscience, The University of Queensland, St Lucia, 4072, QLD, Australia.; Centre for Microscopy and Microanalysis, The University of Queensland, St Lucia, 4072, QLD, Australia., Kress TR; Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Via Adamello 16, 20139, Milan, Italy., Amati B; Department of Experimental Oncology, European Institute of Oncology (IEO) - IRCCS, Via Adamello 16, 20139, Milan, Italy., Littlewood TD; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK., Evan GI; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK. gie20@cam.ac.uk., Wilson CH; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK. chw39@cam.ac.uk.; Department of Pharmacology, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1PD, UK. chw39@cam.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2020 Apr 14; Vol. 11 (1), pp. 1827. Date of Electronic Publication: 2020 Apr 14.
DOI: 10.1038/s41467-020-15552-x
Abstrakt: 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.
Databáze: MEDLINE
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