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在小鼠心脏中重新激活 Myc 转录可释放其增殖能力。

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

机构信息

Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK.

QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.

出版信息

Nat Commun. 2020 Apr 14;11(1):1827. doi: 10.1038/s41467-020-15552-x.

DOI:10.1038/s41467-020-15552-x
PMID:32286286
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7156407/
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.

摘要

目前尚不清楚为什么有些组织对致癌基因 Myc 的有丝分裂效应具有抗性。在这里，我们表明 Myc 的激活会在某些但不是所有器官中引发快速的转录反应，随后是增殖。尽管增殖反应存在差异，但 Myc 在有反应性（肝脏）和无反应性（心脏）组织中的开放元件处与 DNA 结合，但在心脏中不能诱导出强大的转录和增殖反应。我们以心脏作为无反应性组织的范例，表明通过提高正转录延伸因子（P-TEFb）的水平，Myc 驱动的转录可以在成熟的心肌细胞中重新参与，从而引发大量的增殖反应。因此，P-TEFb 活性是决定心脏是否允许 Myc 转录激活的关键限制因素。这些数据提供了对 Myc 转录活性如何确定的更深入了解，并表明可以通过改变 P-TEFb 水平来驱动成年心肌细胞的再生，以治疗心脏肌病。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/27510009fca4/41467_2020_15552_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/f799b406e5b1/41467_2020_15552_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/a323cdc72b92/41467_2020_15552_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/7bfad632af23/41467_2020_15552_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/884e46e737fc/41467_2020_15552_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/0b0180eabb2e/41467_2020_15552_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/06872de6739b/41467_2020_15552_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/777b8bdd41c7/41467_2020_15552_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/937cc6ae3df5/41467_2020_15552_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/27510009fca4/41467_2020_15552_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/f799b406e5b1/41467_2020_15552_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/a323cdc72b92/41467_2020_15552_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/7bfad632af23/41467_2020_15552_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/884e46e737fc/41467_2020_15552_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/0b0180eabb2e/41467_2020_15552_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/06872de6739b/41467_2020_15552_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/777b8bdd41c7/41467_2020_15552_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/937cc6ae3df5/41467_2020_15552_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/549f/7156407/27510009fca4/41467_2020_15552_Fig9_HTML.jpg

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