BET inhibition disrupts transcription but retains enhancer-promoter contact
Enhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes in higher eukaryotes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed in multiple systems at multiple loci and is thoug...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2019
|
| _version_ | 1797081715336806400 |
|---|---|
| author | Nicholas Crump Erica Ballabio Laura Godfrey Ross Thorne Emmanouela Repapi Jon Kerry Marta Tapia Peng Hua Panagis Filippakopoulos James Davies Thomas Milne |
| author_facet | Nicholas Crump Erica Ballabio Laura Godfrey Ross Thorne Emmanouela Repapi Jon Kerry Marta Tapia Peng Hua Panagis Filippakopoulos James Davies Thomas Milne |
| author_sort | Nicholas Crump |
| collection | OXFORD |
| description | Enhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes in higher eukaryotes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed in multiple systems at multiple loci and is thought to be essential for the maintenance of gene expression. Bromodomain and Extra-Terminal domain (BET) and Mediator proteins have been shown capable of forming phase condensates and are thought to be essential for super-enhancer function. Here, we show that targeting of cells with inhibitors of BET proteins or pharmacological degradation of BET protein Bromodomain-containing protein 4 (BRD4) has a strong impact on transcription but very little impact on enhancer-promoter interactions. Dissolving phase condensates reduces BRD4 and Mediator binding at enhancers and can also strongly affect gene transcription, without disrupting enhancer-promoter interactions. These results suggest that activation of transcription and maintenance of enhancer-promoter interactions are separable events. Our findings further indicate that enhancer-promoter interactions are not dependent on high levels of BRD4 and Mediator, and are likely maintained by a complex set of factors including additional activator complexes and, at some sites, CTCF and cohesin. |
| first_indexed | 2024-03-07T01:17:53Z |
| format | Journal article |
| id | oxford-uuid:8f537521-e3a9-4270-aba2-ef610c0f3c46 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:17:53Z |
| publishDate | 2019 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:8f537521-e3a9-4270-aba2-ef610c0f3c462022-03-26T23:03:34ZBET inhibition disrupts transcription but retains enhancer-promoter contactJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8f537521-e3a9-4270-aba2-ef610c0f3c46EnglishSymplectic ElementsSpringer Nature2019Nicholas CrumpErica BallabioLaura GodfreyRoss ThorneEmmanouela RepapiJon KerryMarta TapiaPeng HuaPanagis FilippakopoulosJames DaviesThomas MilneEnhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes in higher eukaryotes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed in multiple systems at multiple loci and is thought to be essential for the maintenance of gene expression. Bromodomain and Extra-Terminal domain (BET) and Mediator proteins have been shown capable of forming phase condensates and are thought to be essential for super-enhancer function. Here, we show that targeting of cells with inhibitors of BET proteins or pharmacological degradation of BET protein Bromodomain-containing protein 4 (BRD4) has a strong impact on transcription but very little impact on enhancer-promoter interactions. Dissolving phase condensates reduces BRD4 and Mediator binding at enhancers and can also strongly affect gene transcription, without disrupting enhancer-promoter interactions. These results suggest that activation of transcription and maintenance of enhancer-promoter interactions are separable events. Our findings further indicate that enhancer-promoter interactions are not dependent on high levels of BRD4 and Mediator, and are likely maintained by a complex set of factors including additional activator complexes and, at some sites, CTCF and cohesin. |
| spellingShingle | Nicholas Crump Erica Ballabio Laura Godfrey Ross Thorne Emmanouela Repapi Jon Kerry Marta Tapia Peng Hua Panagis Filippakopoulos James Davies Thomas Milne BET inhibition disrupts transcription but retains enhancer-promoter contact |
| title | BET inhibition disrupts transcription but retains enhancer-promoter contact |
| title_full | BET inhibition disrupts transcription but retains enhancer-promoter contact |
| title_fullStr | BET inhibition disrupts transcription but retains enhancer-promoter contact |
| title_full_unstemmed | BET inhibition disrupts transcription but retains enhancer-promoter contact |
| title_short | BET inhibition disrupts transcription but retains enhancer-promoter contact |
| title_sort | bet inhibition disrupts transcription but retains enhancer promoter contact |
| work_keys_str_mv | AT nicholascrump betinhibitiondisruptstranscriptionbutretainsenhancerpromotercontact AT ericaballabio betinhibitiondisruptstranscriptionbutretainsenhancerpromotercontact AT lauragodfrey betinhibitiondisruptstranscriptionbutretainsenhancerpromotercontact AT rossthorne betinhibitiondisruptstranscriptionbutretainsenhancerpromotercontact AT emmanouelarepapi betinhibitiondisruptstranscriptionbutretainsenhancerpromotercontact AT jonkerry betinhibitiondisruptstranscriptionbutretainsenhancerpromotercontact AT martatapia betinhibitiondisruptstranscriptionbutretainsenhancerpromotercontact AT penghua betinhibitiondisruptstranscriptionbutretainsenhancerpromotercontact AT panagisfilippakopoulos betinhibitiondisruptstranscriptionbutretainsenhancerpromotercontact AT jamesdavies betinhibitiondisruptstranscriptionbutretainsenhancerpromotercontact AT thomasmilne betinhibitiondisruptstranscriptionbutretainsenhancerpromotercontact |