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Cell Rep. 2018 May 8;23(6):1639-1650. doi: 10.1016/j.celrep.2018.04.031.

A General Framework for Interrogation of mRNA Stability Programs Identifies RNA-Binding Proteins that Govern Cancer Transcriptomes.

Author information

1
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada.
2
Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada.
3
Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
4
International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, Lyon 69008, France.
5
Leeds Institute of Cancer and Pathology, University of Leeds, Cancer Research Building, St. James's University Hospital, Leeds LS9 7TF, UK.
6
Laboratory for Epigenetics & Environment, Centre National de Recherche en Génomique Humaine, CEA-Institut de Biologie Francois Jacob, 2 rue Gaston Crémieux, 91000 Evry, France.
7
Department of Urology, McGill University, Montreal, QC H3G 1A4, Canada.
8
European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
9
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada. Electronic address: hamed.najafabadi@mcgill.ca.
10
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada. Electronic address: yasser.riazalhosseini@mcgill.ca.

Abstract

Widespread remodeling of the transcriptome is a signature of cancer; however, little is known about the post-transcriptional regulatory factors, including RNA-binding proteins (RBPs) that regulate mRNA stability, and the extent to which RBPs contribute to cancer-associated pathways. Here, by modeling the global change in gene expression based on the effect of sequence-specific RBPs on mRNA stability, we show that RBP-mediated stability programs are recurrently deregulated in cancerous tissues. Particularly, we uncovered several RBPs that contribute to the abnormal transcriptome of renal cell carcinoma (RCC), including PCBP2, ESRP2, and MBNL2. Modulation of these proteins in cancer cell lines alters the expression of pathways that are central to the disease and highlights RBPs as driving master regulators of RCC transcriptome. This study presents a framework for the screening of RBP activities based on computational modeling of mRNA stability programs in cancer and highlights the role of post-transcriptional gene dysregulation in RCC.

KEYWORDS:

ESRP2; MBNL2; PCBP2; RNA-binding proteins; gene regulation; mRNA stability; network modeling; regulatory networks; renal cancer

PMID:
29742422
DOI:
10.1016/j.celrep.2018.04.031
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