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Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance

DOI: 10.1126/sciadv.1500723 DOI Help
PMID: 26702435 PMID Help

Authors: O. Fedorov (University of Oxford) , J. Castex (Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg) , C. Tallant Blanco (Structural Genomics Consortium, University of Oxford) , D. R. Owen (Pfizer Worldwide Medicinal Chemistry) , S. Martin (University of Oxford) , M. Aldeghi (University of Oxford) , O. Monteiro (University of Oxford) , P. Filippakopoulos (Structural Genomics Consortium, University of Oxford) , S. Picaud (Structural Genomics Consortium, University of Oxford) , J. D. Trzupek (Pfizer Worldwide Medicinal Chemistry) , B. S. Gerstenberger (Pfizer Worldwide Medicinal Chemistry) , C. Bountra (University of Oxford) , D. Willmann (Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg) , C. Wells (University of Oxford) , M. Philpott (University of Oxford) , C. Rogers (University of Oxford) , P. C. Biggin (University of Oxford) , P. E. Brennan (University of Oxford) , M. E. Bunnage (Pfizer Worldwide Medicinal Chemistry) , R. Schule (Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg) , Thomas Gunther (Klinikum der Universität Freiburg) , Stefan Knapp (Structural Genomics Consortium; Target Discovery Institute, University of Oxford; Johann Wolfgang Goethe-University) , Susanne Muller (Structural Genomics Consortium; Target Discovery Institute, University of Oxford)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Science Advances , VOL 1 , PAGES e1500723 - e1500723

State: Published (Approved)
Published: November 2015

Open Access Open Access

Abstract: Mammalian SWI/SNF [also called Brg/Brahma-associated factors (BAFs)] are evolutionarily conserved chromatin-remodeling complexes regulating gene transcription programs during development and stem cell differentiation. BAF complexes contain an ATP (adenosine 5′-triphosphate)–driven remodeling enzyme (either BRG1 or BRM) and multiple protein interaction domains including bromodomains, an evolutionary conserved acetyl lysine–dependent protein interaction motif that recruits transcriptional regulators to acetylated chromatin. We report a potent and cell active protein interaction inhibitor, PFI-3, that selectively binds to essential BAF bromodomains. The high specificity of PFI-3 was achieved on the basis of a novel binding mode of a salicylic acid head group that led to the replacement of water molecules typically maintained in other bromodomain inhibitor complexes. We show that exposure of embryonic stem cells to PFI-3 led to deprivation of stemness and deregulated lineage specification. Furthermore, differentiation of trophoblast stem cells in the presence of PFI-3 was markedly enhanced. The data present a key function of BAF bromodomains in stem cell maintenance and differentiation, introducing a novel versatile chemical probe for studies on acetylation-dependent cellular processes controlled by BAF remodeling complexes.

Diamond Keywords: Epigenetics

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I03-Macromolecular Crystallography

Added On: 10/12/2015 15:32

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Genetics Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)