title: Mapping the chemical chromatin reactivation landscape identifies BRD4-TAF1 cross-talk.
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.
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Sara
authors.initials: S
authors.lastname: Sdelci
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Charles-Hugues
authors.initials: CH
authors.lastname: Lardeau
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tallant
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Freya
authors.initials: F
authors.lastname: Klepsch
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Björn
authors.initials: B
authors.lastname: Klaiber
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
authors.forename: James
authors.initials: J
authors.lastname: Bennett
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Philipp
authors.initials: P
authors.lastname: Rathert
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Schuster
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Penz
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Giulio
authors.identifier: 0000-0002-0570-1768
authors.initials: G
authors.lastname: Superti-Furga
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.|Max Planck Institute for Informatics, Saarbrücken, Germany.
authors.forename: Christoph
authors.identifier: 0000-0001-6091-3088
authors.initials: C
authors.lastname: Bock
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Johannes
authors.identifier: 0000-0001-8810-6835
authors.initials: J
authors.lastname: Zuber
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
authors.forename: Kilian V M
authors.identifier: 0000-0002-1103-5300
authors.initials: KV
authors.lastname: Huber
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.|Johann Wolfgang Goethe-University, Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Stefan
authors.identifier: 0000-0003-0855-8343
authors.initials: S
authors.lastname: Kubicek
mesh_terms: D018797:Cell Cycle Proteins; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000072417:Protein Domains / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D035381:TATA-Binding Protein Associated Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D035362:Transcription Factor TFIID / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D051548:Histone Acetyltransferases; D009687:Nuclear Proteins; D054852:Small Molecule Libraries; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C069001:TATA-binding protein associated factor 250 kDa