期刊
SCIENCE ADVANCES
卷 1, 期 10, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.1500723
关键词
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资金
- Structural Genomics Consortium [1097737]
- AbbVie
- Bayer
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Canadian Institutes for Health Research
- Genome Canada
- GlaxoSmithKline
- Janssen
- Lilly Canada
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Takeda
- Wellcome Trust [092809/Z/10/Z, 095751/Z/11/Z]
- Else Kroner-Fresenius-Stiftung [2012_A72]
- Engineering and Physical Sciences Research Council
- Doctoral Training Centre
- [ERC 3228444 LSD1]
- [SFB992]
- [SFB746]
- [Schu 688/12-1]
- EPSRC [EP/L000253/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/L000253/1, 1233347] Funding Source: researchfish
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.
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