A General Framework for Interrogation of mRNA Stability Programs Identifies RNA-Binding Proteins that Govern Cancer Transcriptomes
Gabrielle Perron,
Pouria Jandaghi,
Shraddha Solanki,
Maryam Safisamghabadi,
Cristina Storoz,
Mehran Karimzadeh,
Andreas I. Papadakis,
Madeleine Arseneault,
Ghislaine Scelo,
Rosamonde E. Banks,
Jorg Tost,
Mark Lathrop,
Simon Tanguay,
Alvis Brazma,
Sidong Huang,
Fadi Brimo,
Hamed S. Najafabadi,
Yasser Riazalhosseini
Affiliations
Gabrielle Perron
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada
Pouria Jandaghi
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada
Shraddha Solanki
Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada
Maryam Safisamghabadi
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada
Cristina Storoz
Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada
Mehran Karimzadeh
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada
Andreas I. Papadakis
Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada
Madeleine Arseneault
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada
Ghislaine Scelo
International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, Lyon 69008, France
Rosamonde E. Banks
Leeds Institute of Cancer and Pathology, University of Leeds, Cancer Research Building, St. James’s University Hospital, Leeds LS9 7TF, UK
Jorg Tost
Laboratory for Epigenetics & Environment, Centre National de Recherche en Génomique Humaine, CEA-Institut de Biologie Francois Jacob, 2 rue Gaston Crémieux, 91000 Evry, France
Mark Lathrop
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada
Simon Tanguay
Department of Urology, McGill University, Montreal, QC H3G 1A4, Canada
Alvis Brazma
European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK
Sidong Huang
Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada
Fadi Brimo
Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada
Hamed S. Najafabadi
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada; Corresponding author
Yasser Riazalhosseini
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada; Corresponding author
Summary: 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. : Perron et al. develop a computational approach that models the functional activity of RBPs in individual cancer samples by monitoring their associated RNA stability programs. Applying this method to renal cell carcinoma transcriptomes, the authors identify RBPs that enhance cancer-associated pathways including hypoxia and cell cycle. Keywords: RNA-binding proteins, gene regulation, mRNA stability, renal cancer, regulatory networks, network modeling, MBNL2, PCBP2, ESRP2
