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Series GSE71776 Query DataSets for GSE71776
Status Public on Jun 12, 2016
Title ChIPSeq of MV4;11 cell treated with DMSO, I-BET, SGC0946 and combination of I-BET and SGC0946
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Central to the molecular pathogenesis of MLL leukaemia is the abnormal co-optation of members of transcription complexes including disrupter of telomeric silencing 1-like (DOT1L) and bromodomain containing protein 4 (BRD4). Consequently, targeted therapies against DOT1L and BRD4 are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukaemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation we find that native BRD4 and DOT1L exist in largely separate protein complexes. Genetic disruption or small molecule inhibition of BRD4 and DOT1L shows marked synergistic activity against MLL-FP leukaemia cell lines, primary human leukaemia cells and murine leukaemia models. Mechanistically, we find a previously unrecognised functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in close proximity to superenhancers. DOT1L via H3K79me2 facilitates the deposition of histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide novel insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this poor prognostic disease.
Overall design ChIPSeq of MV4;11 cell treated with DMSO, I-BET, SGC0946 and combination of I-BET and SGC0946
Contributor(s) Dawson M, Gilan O, Lam E
Citation(s) 27294782
Submission date Aug 06, 2015
Last update date May 15, 2019
Contact name Mark Dawson
Organization name Peter MacCallum Cancer Centre
Street address 305 Grattan Street
City Melbourne
State/province VIC
ZIP/Postal code 3000
Country Australia
Platforms (1)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
Samples (16)
GSM1845134 DMSO_H3K27ac_ChIP
GSM1845135 DMSO_H3K79me2_ChIP
This SubSeries is part of SuperSeries:
GSE71780 Functional interdependency of BRD4 and DOT1L in MLL leukaemia
BioProject PRJNA292067
SRA SRP062098

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Supplementary file Size Download File type/resource
GSE71776_RAW.tar 16.2 Mb (http)(custom) TAR (of BED)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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