MLL-AF4 binds directly to a BCL-2 specific enhancer and modulates H3K27 acetylation.
Survival rates for children and adults carrying mutations in the Mixed Lineage Leukemia (MLL) gene continue to have a very poor prognosis. The most common MLL mutation in ALL is the t(4;11)(q21;q23) chromosome translocation that fuses MLL in frame with the AF4 gene producing MLL-AF4 and AF4-MLL fusi...
| المؤلفون الرئيسيون: | , , , , , , , , , , |
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| التنسيق: | Journal article |
| اللغة: | English |
| منشور في: |
Elsevier
2016
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| _version_ | 1826276493894877184 |
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| author | Godfrey, L Kerry, J Thorne, R Repapi, E Davies, J Tapia, M Ballabio, E Hughes, J Geng, H Konopleva, M Milne, T |
| author_facet | Godfrey, L Kerry, J Thorne, R Repapi, E Davies, J Tapia, M Ballabio, E Hughes, J Geng, H Konopleva, M Milne, T |
| author_sort | Godfrey, L |
| collection | OXFORD |
| description | Survival rates for children and adults carrying mutations in the Mixed Lineage Leukemia (MLL) gene continue to have a very poor prognosis. The most common MLL mutation in ALL is the t(4;11)(q21;q23) chromosome translocation that fuses MLL in frame with the AF4 gene producing MLL-AF4 and AF4-MLL fusion proteins. Previously, we demonstrated that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. Here, we perform a detailed analysis of MLL-AF4 regulation of the entire BCL-2 family. By measuring nascent RNA production in MLL-AF4 knockdowns, we find that of all the BCL-2 family genes, MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1, and also represses BIM via binding of the polycomb group repressor 1 (PRC1) complex component CBX8. We further analyze MLL-AF4 activation of the BCL-2 gene using Capture C and identify a BCL-2 specific enhancer, consisting of two clusters of H3K27Ac at the 3’end of the gene. Loss of MLL-AF4 activity results in a reduction of H3K79me3 levels in the gene body and H3K27Ac levels at the 3’ BCL-2 enhancer, revealing a novel regulatory link between these two histone marks and MLL-AF4 mediated activation of BCL-2. |
| first_indexed | 2024-03-06T23:14:48Z |
| format | Journal article |
| id | oxford-uuid:66c1a612-0114-4351-909d-9a6bf5a58287 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:14:48Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:66c1a612-0114-4351-909d-9a6bf5a582872022-03-26T18:33:58ZMLL-AF4 binds directly to a BCL-2 specific enhancer and modulates H3K27 acetylation.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:66c1a612-0114-4351-909d-9a6bf5a58287EnglishSymplectic Elements at OxfordElsevier2016Godfrey, LKerry, JThorne, RRepapi, EDavies, JTapia, MBallabio, EHughes, JGeng, HKonopleva, MMilne, TSurvival rates for children and adults carrying mutations in the Mixed Lineage Leukemia (MLL) gene continue to have a very poor prognosis. The most common MLL mutation in ALL is the t(4;11)(q21;q23) chromosome translocation that fuses MLL in frame with the AF4 gene producing MLL-AF4 and AF4-MLL fusion proteins. Previously, we demonstrated that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. Here, we perform a detailed analysis of MLL-AF4 regulation of the entire BCL-2 family. By measuring nascent RNA production in MLL-AF4 knockdowns, we find that of all the BCL-2 family genes, MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1, and also represses BIM via binding of the polycomb group repressor 1 (PRC1) complex component CBX8. We further analyze MLL-AF4 activation of the BCL-2 gene using Capture C and identify a BCL-2 specific enhancer, consisting of two clusters of H3K27Ac at the 3’end of the gene. Loss of MLL-AF4 activity results in a reduction of H3K79me3 levels in the gene body and H3K27Ac levels at the 3’ BCL-2 enhancer, revealing a novel regulatory link between these two histone marks and MLL-AF4 mediated activation of BCL-2. |
| spellingShingle | Godfrey, L Kerry, J Thorne, R Repapi, E Davies, J Tapia, M Ballabio, E Hughes, J Geng, H Konopleva, M Milne, T MLL-AF4 binds directly to a BCL-2 specific enhancer and modulates H3K27 acetylation. |
| title | MLL-AF4 binds directly to a BCL-2 specific enhancer and modulates H3K27 acetylation. |
| title_full | MLL-AF4 binds directly to a BCL-2 specific enhancer and modulates H3K27 acetylation. |
| title_fullStr | MLL-AF4 binds directly to a BCL-2 specific enhancer and modulates H3K27 acetylation. |
| title_full_unstemmed | MLL-AF4 binds directly to a BCL-2 specific enhancer and modulates H3K27 acetylation. |
| title_short | MLL-AF4 binds directly to a BCL-2 specific enhancer and modulates H3K27 acetylation. |
| title_sort | mll af4 binds directly to a bcl 2 specific enhancer and modulates h3k27 acetylation |
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