 |
 |
GEO help: Mouse over screen elements for information. |
|
| 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)
|
|
| Relations |
| BioProject |
PRJNA487522 |
| SRA |
SRP158660 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE118954_RAW.tar |
10.7 Gb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
|
|
|
|
 |
Less...
More...