Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance.
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 en...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
American Association for the Advancement of Science
2015
|
| _version_ | 1797095461270585344 |
|---|---|
| author | Fedorov, O Castex, J Tallant, C Owen, D Martin, S Aldeghi, M Monteiro, O Filippakopoulos, P Picaud, S Trzupek, J Gerstenberger, B Bountra, C Willmann, D Wells, C Philpott, M Rogers, C Biggin, P Brennan, P Bunnage, M Schüle, R Günther, T Knapp, S Müller, S |
| author_facet | Fedorov, O Castex, J Tallant, C Owen, D Martin, S Aldeghi, M Monteiro, O Filippakopoulos, P Picaud, S Trzupek, J Gerstenberger, B Bountra, C Willmann, D Wells, C Philpott, M Rogers, C Biggin, P Brennan, P Bunnage, M Schüle, R Günther, T Knapp, S Müller, S |
| author_sort | Fedorov, O |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T04:28:08Z |
| format | Journal article |
| id | oxford-uuid:cd5bb46a-0b27-4b2a-a7c8-baad26dc7ed5 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:28:08Z |
| publishDate | 2015 |
| publisher | American Association for the Advancement of Science |
| record_format | dspace |
| spelling | oxford-uuid:cd5bb46a-0b27-4b2a-a7c8-baad26dc7ed52022-03-27T07:28:17ZSelective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:cd5bb46a-0b27-4b2a-a7c8-baad26dc7ed5EnglishSymplectic Elements at OxfordAmerican Association for the Advancement of Science2015Fedorov, OCastex, JTallant, COwen, DMartin, SAldeghi, MMonteiro, OFilippakopoulos, PPicaud, STrzupek, JGerstenberger, BBountra, CWillmann, DWells, CPhilpott, MRogers, CBiggin, PBrennan, PBunnage, MSchüle, RGünther, TKnapp, SMüller, SMammalian 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. |
| spellingShingle | Fedorov, O Castex, J Tallant, C Owen, D Martin, S Aldeghi, M Monteiro, O Filippakopoulos, P Picaud, S Trzupek, J Gerstenberger, B Bountra, C Willmann, D Wells, C Philpott, M Rogers, C Biggin, P Brennan, P Bunnage, M Schüle, R Günther, T Knapp, S Müller, S Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance. |
| title | Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance. |
| title_full | Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance. |
| title_fullStr | Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance. |
| title_full_unstemmed | Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance. |
| title_short | Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance. |
| title_sort | selective targeting of the brg pb1 bromodomains impairs embryonic and trophoblast stem cell maintenance |
| work_keys_str_mv | AT fedorovo selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT castexj selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT tallantc selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT owend selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT martins selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT aldeghim selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT monteiroo selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT filippakopoulosp selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT picauds selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT trzupekj selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT gerstenbergerb selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT bountrac selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT willmannd selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT wellsc selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT philpottm selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT rogersc selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT bigginp selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT brennanp selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT bunnagem selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT schuler selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT gunthert selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT knapps selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance AT mullers selectivetargetingofthebrgpb1bromodomainsimpairsembryonicandtrophoblaststemcellmaintenance |