2. Academic Validation
  3. Mapping the chemical chromatin reactivation landscape identifies BRD4-TAF1 cross-talk

Mapping the chemical chromatin reactivation landscape identifies BRD4-TAF1 cross-talk

  • Nat Chem Biol. 2016 Jul;12(7):504-10. doi: 10.1038/nchembio.2080.
Sara Sdelci 1,  Charles-Hugues Lardeau 1 2,  Cynthia Tallant 3 4,  Freya Klepsch 1,  Björn Klaiber 1,  James Bennett 3 4,  Philipp Rathert 5,  Michael Schuster 1,  Thomas Penz 1,  Oleg Fedorov 3 4,  Giulio Superti-Furga 1 6,  Christoph Bock 1 7 8,  Johannes Zuber 5,  Kilian V M Huber 1 3 4,  Stefan Knapp 3 4 9,  Susanne Müller 3 4,  Stefan Kubicek 1 2
Affiliations

Affiliations

  • 1 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 2 Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 3 Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
  • 4 Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
  • 5 Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
  • 6 Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
  • 7 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
  • 8 Max Planck Institute for Informatics, Saarbrücken, Germany.
  • 9 Johann Wolfgang Goethe-University, Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Frankfurt am Main, Germany.
PMID: 27159579 DOI: 10.1038/nchembio.2080
Abstract

Bromodomain-containing proteins of the BET family recognize histone lysine acetylation and mediate transcriptional activation of target genes such as the MYC oncogene. Pharmacological inhibitors of BET domains promise therapeutic benefits in a variety of cancers. We performed a high-diversity chemical compound screen for agents capable of modulating BRD4-dependent heterochromatization of a generic reporter in human cells. In addition to known and new compounds targeting BRD4, we identified small molecules that mimic BRD4 inhibition without direct engagement. One such compound was a potent inhibitor of the second bromodomain of TAF1. Using this inhibitor, we discovered that TAF1 synergizes with BRD4 to control proliferation of Cancer cells, making TAF1 an attractive epigenetic target in cancers driven by MYC.

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