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Series GSE118954 Query DataSets for GSE118954
Status Public on Aug 31, 2018
Title Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary A methionine substitution at lysine 27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits PRC2 in a dominant negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found this interaction on chromatin is transient with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-chromatin suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to K27M leading to a failure to spread H3K27me3 at distinct foci. In turn, levels of Polycomb antagonists such as H3K36me2 are elevated suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity.
Overall design Role of PRC2 in H3K27M pediatric glioma
Contributor(s) Stafford JM, Lee C, Voigt P, Descostes N, Saldaña-Meyer R, Yu J, Leroy G, Oksuz O, Chapman JR, Suarez F, Modrek AS, Bayin NS, Placantonakis DG, Karajannis MA, Snuderl M, Ueberheide B, Reinberg D
Citation(s) 30402543
Submission date Aug 23, 2018
Last update date Mar 26, 2019
Contact name nicolas descostes
Organization name EMBL
Department Bioinformatics
Street address via Ramarini 32
City Monterotondo
ZIP/Postal code 00015
Country Italy
Platforms (1)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (64)
GSM3354593 EZH2_K27M_0Hr
GSM3354594 EZH2_K27M_12hr
GSM3354595 EZH2_K27M_24hr
BioProject PRJNA487522
SRA SRP158660

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Supplementary file Size Download File type/resource
GSE118954_RAW.tar 10.7 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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