Transite: A Computational Motif-Based Analysis Platform That Identifies RNA-Binding Proteins Modulating Changes in Gene Expression
Konstantin Krismer,
Molly A. Bird,
Shohreh Varmeh,
Erika D. Handly,
Anna Gattinger,
Thomas Bernwinkler,
Daniel A. Anderson,
Andreas Heinzel,
Brian A. Joughin,
Yi Wen Kong,
Ian G. Cannell,
Michael B. Yaffe
Affiliations
Konstantin Krismer
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 32 Vassar Street, Cambridge, MA 02139, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Department for Medical and Bioinformatics, University of Applied Sciences Upper Austria, Softwarepark 11, 4232 Hagenberg, Austria
Molly A. Bird
Center for Precision Cancer Medicine, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Shohreh Varmeh
Center for Precision Cancer Medicine, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA
Erika D. Handly
Center for Precision Cancer Medicine, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Anna Gattinger
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Department for Medical and Bioinformatics, University of Applied Sciences Upper Austria, Softwarepark 11, 4232 Hagenberg, Austria
Thomas Bernwinkler
Center for Precision Cancer Medicine, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Department for Medical and Bioinformatics, University of Applied Sciences Upper Austria, Softwarepark 11, 4232 Hagenberg, Austria
Daniel A. Anderson
Synthetic Biology Center, Massachusetts Institute of Technology, 500 Technology Square, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Andreas Heinzel
Department for Medical and Bioinformatics, University of Applied Sciences Upper Austria, Softwarepark 11, 4232 Hagenberg, Austria
Brian A. Joughin
Center for Precision Cancer Medicine, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Yi Wen Kong
Center for Precision Cancer Medicine, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Corresponding author
Ian G. Cannell
Center for Precision Cancer Medicine, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Corresponding author
Michael B. Yaffe
Center for Precision Cancer Medicine, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Divisions of Acute Care Surgery, Trauma and Surgical Critical Care, and Surgical Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA; Corresponding author
Summary: RNA-binding proteins (RBPs) play critical roles in regulating gene expression by modulating splicing, RNA stability, and protein translation. Stimulus-induced alterations in RBP function contribute to global changes in gene expression, but identifying which RBPs are responsible for the observed changes remains an unmet need. Here, we present Transite, a computational approach that systematically infers RBPs influencing gene expression through changes in RNA stability and degradation. As a proof of principle, we apply Transite to RNA expression data from human patients with non-small-cell lung cancer whose tumors were sampled at diagnosis or after recurrence following treatment with platinum-based chemotherapy. Transite implicates known RBP regulators of the DNA damage response and identifies hnRNPC as a new modulator of chemotherapeutic resistance, which we subsequently validated experimentally. Transite serves as a framework for the identification of RBPs that drive cell-state transitions and adds additional value to the vast collection of publicly available gene expression datasets.
