Format

Send to

Choose Destination
Sci Adv. 2018 Oct 31;4(10):eaau5935. doi: 10.1126/sciadv.aau5935. eCollection 2018 Oct.

Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma.

Author information

1
Department of Biochemistry and Molecular Pharmacology, NYUSoM, New York, NY, USA.
2
Howard Hughes Medical Institute, Chevy Chase, MD, USA.
3
Proteomics Laboratory, NYUSoM, New York, NY, USA.
4
Laura and Isaac Perlmutter Cancer Center, NYUSoM, New York, NY, USA.
5
Department of Pediatrics, NYUSoM, New York, NY, USA.
6
Department of Neurosurgery, NYUSoM, New York, NY, USA.
7
Kimmel Center for Stem Cell Biology, NYUSoM, New York, NY, USA.
8
Neuroscience Institute, NYUSoM, New York, NY, USA.
9
Department of Pathology, Division of Neuropathology, NYUSoM, New York, NY, USA.

Abstract

A methionine substitution at lysine-27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (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 that this interaction on chromatin is transient, with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-containing chromatin, suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to H3K27M, leading to the failure to spread H3K27me from PRC2 recruitment sites and consequently abrogating PRC2's ability to establish H3K27me2-3 repressive chromatin domains. 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.

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center