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Series GSE83671 Query DataSets for GSE83671
Status Public on Jan 12, 2017
Title MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia.
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
Summary Understanding the underlying molecular mechanisms of defined cancers is crucial for effective personalized therapies. Translocations of the Mixed Lineage Leukemia (MLL) gene produce fusion proteins such as MLL-AF4 that disrupt epigenetic pathways and cause poor prognosis leukemias. Here we find that MLL-AF4 occupies a subset of unmethylated CG-enriched genes in combination with its cofactors Menin/LEDGF and ENL. MLL-AF4 mainly displays a punctate binding pattern near gene promoters, but we also observe a second less common pattern where MLL-AF4 spreads into the gene body and is associated with increased transcription and increased histone H3 lysine 79 methylation (H3K79me2/3). Compared to other H3K79me2/3 marked genes, MLL-AF4 spreading genes are more sensitive to inhibitors of the H3K79 methyltransferase DOT1L. This sensitivity mediates synergistic interactions with additional targeted drug treatments. Therefore, epigenetic spreading and enhanced susceptibility to epidrugs provides a potential new Achilles heel for guiding combination therapies in humans.
Overall design Examination of gene expression, histone marks and multiple chromatin proteins in MLL leukemia cell lines and patient samples
Contributor(s) Milne TA, Kerry J
Citation(s) 28076791
Submission date Jun 23, 2016
Last update date May 15, 2019
Contact name Thomas Milne
Organization name Weatherall Institute of Molecular Medicine
Department Molecular Haematology Unit
Street address John Radcliffe Hospital
City Oxford
ZIP/Postal code OX3 9DS
Country United Kingdom
Platforms (3)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (59)
GSM2212231 SEM_H3K36me3_ChIPSeq
GSM2212232 SEM_H3K36me3_InputDNA
GSM2212233 SEM_BioCAPseq
BioProject PRJNA326673
SRA SRP077016

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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE83671_EPZ5676_rpkm.txt.gz 989.2 Kb (ftp)(http) TXT
GSE83671_RAW.tar 865.7 Mb (http)(custom) TAR (of BED, BW)
GSE83671_SEM_nascent_rpkm_table.txt.gz 473.0 Kb (ftp)(http) TXT
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Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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