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Series GSE118440 Query DataSets for GSE118440
Status Public on Jun 10, 2019
Title 2-hydroxyglutarate inhibits transcription factor mediated differentiation by preventing H3K9 demethylation
Organism Mus musculus
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary ATAC-seq associates impairment of myogenic differentiation in cells with an IDH2 mutation with differences in chromatin accessibility. Differences are especially apparent in regions flanking binding sites for myogenic regulatory factors and key myogenesis noncoding RNA linc-MD1.

Oncogenic IDH1/2 mutations produce 2-hydroxyglutarate (2HG), resulting in competitive inhibition of DNA and protein demethylation. IDH-mutant cancer cells show an inability to differentiate but whether 2HG accumulation is sufficient to perturb differentiation directed by lineage-specifying transcription factors is unknown. A MyoD-driven model was used to study the role of IDH mutations in the differentiation of mesenchymal cells. The presence of 2HG produced by oncogenic IDH2 blocks the ability of MyoD to drive differentiation into myotubes. DNA 5mC hypermethylation is dispensable while H3K9 hypermethylation is required for this differentiation block. IDH2-R172K mutation results in H3K9 hypermethylation and impaired accessibility at myogenic chromatin regions but does not result in genome-wide decrease in accessibility. The results demonstrate the ability of the oncometabolite to 2HG block transcription factor-mediated differentiation in a molecularly defined system.
Overall design ATAC-seq of mouse 10T1/2 cells, WT for IDH2 vs. R172K mutation of IDH2, with tamoxifen-inducible differentiation via activation of MyoD-ER.
ChIP-seq of mouse 10T1/2 cells, WT for IDH2 vs. R172K mutation of IDH2, with tamoxifen-inducible differentiation via activation of MyoD-ER, with and without UNC0638, a G9a/GLP inhibitor.
Contributor(s) Schvartzman JM, Reuter V, Koche RP, Thompson C
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Submission date Aug 12, 2018
Last update date Jun 13, 2019
Contact name Richard Koche
Organization name Sloan Kettering Institute
Lab Center for Epigenetics Research
Street address 430 East 67th Street
City New York
State/province NY
ZIP/Postal code 10065
Country USA
Platforms (2)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (29)
GSM3330229 Mouse 10T1/2, Wildtype + Tamoxifen 1 [ATAC-seq]
GSM3330230 Mouse 10T1/2, Wildtype + Tamoxifen 2 [ATAC-seq]
GSM3330231 Mouse 10T1/2, Wildtype + Tamoxifen 3 [ATAC-seq]
BioProject PRJNA485652
SRA SRP157393

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Supplementary file Size Download File type/resource
GSE118440_RAW.tar 15.7 Gb (http)(custom) TAR (of BW)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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