Transcriptome-wide characterization of the endogenous miR-34A-p53 tumor suppressor network
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Nardin Samuel1,2,3, Gavin Wilson3,4, Badr Id Said2, Anna Pan2, Genevieve Deblois5, Nicholas W. Fischer6, Roumiana Alexandrova7, Guillermo Casallo7, Tara Paton7, Mathieu Lupien5, Jean Gariepy6, Daniele Merico7, Thomas J. Hudson1,3,4, David Malkin1,2,8
1Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Canada
2Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Canada
3Ontario Institute for Cancer Research, Toronto, Canada
4Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, Canada
5Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
6Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Canada
7The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada
8Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
David Malkin, email: [email protected]
Keywords: miR-34A, p53, TP53, cell cycle, non-coding RNA
Received: April 07, 2016 Accepted: May 19, 2016 Published: July 06, 2016
microRNA-34A is a critical component of the p53 network and expression of miR- 34A is down-regulated by promoter hypermethylation or focal deletions in numerous human cancers. Although miR-34A deregulation may be an important driver in cancer, the endogenous role of this microRNA in cellular homeostasis is not well characterized. To address this knowledge gap, we aimed to determine the transcriptional landscape of the miR-34A-p53 axis in non-transformed cells. Using primary skin-derived fibroblast cell lines from patients who developed childhood cancers, and who harbor either germline TP53 mutations or are TP53 wild type, we sought to characterize the transcriptional response to miR-34A modulation. Through transcriptome-wide RNA-Sequencing, we show for the first time that in human non- transformed cells harboring TP53 mutations, miR-34A functions in a noncanonical manner to influence noncoding RNA networks, including RNA components of the minor (U12) spliceosome, as well as TP53-dependent and independent epigenetic pathways. miR- 34A-regulated transcripts include known cell cycle mediators and abrogation of miR-34A leads to a TP53-dependent increase in the fraction of cells in G2/M. Collectively, these results provide a framework for understanding the endogenous role of the miR-34A signaling axis and identify novel transcripts and pathways regulated by the essential miR-34A-p53 tumor suppressor network.
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