DataSets / Project home (BET rewiring)
Interactome rewiring following pharmacological targeting of BET bromodomains
First Author: Jean-Philippe Lambert and Sarah Picaud
Abstract:
  Targeting bromodomains (BRDs) of the bromo-and extra-terminal (BET) family has offered opportunities for the therapeutic intervention of cancer and other diseases. However, there has not been a systematic study of the consequences of BET inhibition on the interactions established by members of this important protein scaffolding family. Here, we profiled the interactomes of BRD2, BRD3, BRD4 and BRDT during a time course of treatment with the pan-BET inhibitor JQ1, revealing broad rewiring of the interaction landscape, with three distinct classes of behaviour for the 603 unique interactors identified. We report a group of proteins that associate with BET BRDs through canonical and new binding modes that dissociate upon inhibitor treatment. We further establish two classes of extra-terminal (ET)-domain binding motifs that mediate acetylation-independent interactions, offering attractive possibilities for specific therapeutic modulation. Lastly, we identify unexpected increased interactions following JQ1 treatment and define new BRD3 functions in ribosome biogenesis and gene expression modulated via BET-protein inter-regulation and competition for common targets. Together, our data outline the contributions of BET protein modules to their interactomes and help better understand pharmacological rewiring.

This dataset is part of a manuscript accepted for publication in Molecular Cell.

Please contact Anne-Claude Gingras (gingras@lunenfeld.ca) for details on the proteomics aspects and Panagis Filippakopoulos (panagis.filippakopoulos@sgc.ox.ac.uk) for all questions regarding biophysical and structural studies.


Navigating this website

• The data included here is by default filtered at a Bayesian false discovery rate of ≤1%, as calculated by SAINTexpress; unselect the "high confidence" buttons to view all data. You can also download a complete interactome table through the Supplementary data section (left).

Select "Explore baits" (left) to view all baits profiled, organized alphabetically (view as a list). Clicking on a bait will retrieve all its interactors (high confidence by default) and indicate which interactions are already deposited in the BioGRID and IntAct databases.

• Selecting multiple baits (or all baits) will enable a download of the SAINT result file that can be opened at ProHits-viz for visualization and further exploration.

• Also see the many links to excellent external resources for the baits and/or preys, including ProteinAtlas, ProteomicsDB, NCBI Gene, GeneCards and UniProt.

• Search for a bait or prey by Official Gene Symbol through the "Search" tab on left (or at the top). You will be able to search across all projects you have access to.

• Please see the Supplementary Data tab for additional figures, tables and input files for Cytoscape and prohits-viz.

Note that the mass spectrometry data has been deposited at MassIVE.


Copyright © 2012 Gingras labs, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.