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

2018 ◽  
Vol 4 (10) ◽  
pp. eaau5935 ◽  
Author(s):  
James M. Stafford ◽  
Chul-Hwan Lee ◽  
Philipp Voigt ◽  
Nicolas Descostes ◽  
Ricardo Saldaña-Meyer ◽  
...  
Keyword(s):  
Quantitative Proteomics ◽  
Histone H3 ◽  
Dominant Negative ◽  
Polycomb Repressive Complex ◽  
Chromatin Domains ◽  
Pediatric Glioma ◽  
Polycomb Repressive Complex 2 ◽  
Repressive Chromatin ◽  
Paradoxical Effects ◽  
Diffuse Intrinsic Pontine Gliomas

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.

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

2018 ◽  
Author(s):  
James M. Stafford ◽  
Chul-Hwan Lee ◽  
Philipp Voigt ◽  
Nicolas Descostes ◽  
Ricardo Saldaña-Meyer ◽  
...  
Keyword(s):  
Quantitative Proteomics ◽  
Histone H3 ◽  
Dominant Negative ◽  
Pediatric Glioma ◽  
Multiple Modes ◽  
Paradoxical Effects ◽  
Diffuse Intrinsic Pontine Gliomas

ABSTRACTA 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.

An overview of the development of EED inhibitors to disable PRC2 function

2021 ◽  
Author(s):  
Kai-Lu Liu ◽  
KongKai Zhu ◽  
Hua Zhang
Keyword(s):  
Histone H3 ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2

The polycomb repressive complex 2 (PRC2) catalyzes the methylation of histone H3 lysine 27 (H3K27) and the enrichment of its catalytic product H3K27me3 is responsible for the silencing of tumor...

Convergent evolution of chromatin modification by structurally distinct enzymes: comparative enzymology of histone H3 Lys27 methylation by human polycomb repressive complex 2 and vSET

2013 ◽  
Vol 453 (2) ◽  
pp. 241-247 ◽  
Author(s):  
Brooke M. Swalm ◽  
Kenneth K. Hallenbeck ◽  
Christina R. Majer ◽  
Lei Jin ◽  
Margaret Porter Scott ◽  
...  
Keyword(s):  
Active Site ◽  
Convergent Evolution ◽  
Epigenetic Modification ◽  
Chromatin Modification ◽  
Histone H3 ◽  
Genetic Alterations ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2 ◽  
H3k27 Methylation ◽  
Comparative Enzymology

H3K27 (histone H3 Lys27) methylation is an important epigenetic modification that regulates gene transcription. In humans, EZH (enhancer of zeste homologue) 1 and EZH2 are the only enzymes capable of catalysing methylation of H3K27. There is great interest in understanding structure–function relationships for EZH2, as genetic alterations in this enzyme are thought to play a causal role in a number of human cancers. EZH2 is challenging to study because it is only active in the context of the multi-subunit PRC2 (polycomb repressive complex 2). vSET is a viral lysine methyltransferase that represents the smallest protein unit capable of catalysing H3K27 methylation. The crystal structure of this minimal catalytic protein has been solved and researchers have suggested that vSET might prove useful as an EZH2 surrogate for the development of active site-directed inhibitors. To test this proposition, we conducted comparative enzymatic analysis of human EZH2 and vSET and report that, although both enzymes share similar preferences for methylation of H3K27, they diverge in terms of their permissiveness for catalysing methylation of alternative histone lysine sites, their relative preferences for utilization of multimeric macromolecular substrates, their active site primary sequences and, most importantly, their sensitivity to inhibition by drug-like small molecules. The cumulative data led us to suggest that EZH2 and vSET have very distinct active site structures, despite the commonality of the reaction catalysed by the two enzymes. Hence, the EZH2 and vSET pair of enzymes represent an example of convergent evolution in which distinct structural solutions have developed to solve a common catalytic need.

scholarly journals Combinations of maternal-specific repressive epigenetic marks in the endosperm control seed dormancy

2020 ◽  
Author(s):  
Hikaru Sato ◽  
Juan Santos-González ◽  
Claudia Köhler
Keyword(s):  
Seed Dormancy ◽  
Histone H3 ◽  
Epigenetic Modifications ◽  
Polycomb Repressive Complex ◽  
Epigenetic Marks ◽  
Polycomb Repressive Complex 2 ◽  
Adaptive Trait ◽  
Control Seed ◽  
Histone 3

AbstractPolycomb Repressive Complex 2 (PRC2)-mediated trimethylation of histone H3 on lysine 27 (H3K27me3) and methylation of histone 3 on lysine 9 (H3K9me) are two repressive epigenetic modifications that are typically localized in distinct regions of the genome. For reasons unknown, however, they co-occur in some organisms and special tissue types. In this study, we show that maternal alleles marked by H3K27me3 in the Arabidopsis endosperm were targeted by the H3K27me3 demethylase REF6 and became activated during germination. In contrast, maternal alleles marked by H3K27me3, H3K9me2, and CHGm were protected from REF6 targeting and remained silenced. Our study unveils that combinations of different repressive epigenetic modifications time a key adaptive trait by modulating access of REF6.

scholarly journals The Histone H3 Lysine 9 Methyltransferases G9a and GLP Regulate Polycomb Repressive Complex 2-Mediated Gene Silencing

2014 ◽  
Vol 53 (2) ◽  
pp. 277-289 ◽  
Author(s):  
Chiara Mozzetta ◽  
Julien Pontis ◽  
Lauriane Fritsch ◽  
Philippe Robin ◽  
Manuela Portoso ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Histone H3 ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2

scholarly journals Distinct stimulatory mechanisms regulate the catalytic activity of Polycomb Repressive Complex 2 (PRC2)

2017 ◽  
Author(s):  
Chul-Hwan Lee ◽  
Marlene Holder ◽  
Daniel Grau ◽  
Ricardo Saldana-Meyer ◽  
Rais Ahmad Ganai ◽  
...  
Keyword(s):  
Cellular Differentiation ◽  
Expression Patterns ◽  
Histone H3 ◽  
Gene Expression Patterns ◽  
Allosteric Modulators ◽  
Polycomb Repressive Complex ◽  
Allosteric Activation ◽  
Catalytic Subunits ◽  
Polycomb Repressive Complex 2 ◽  
The Difference

AbstractThe maintenance of gene expression patterns during metazoan development is carried out, in part, by the actions of the Polycomb Repressive Complex 2 (PRC2). PRC2 catalyzes mono-, di-and trimethylation of histone H3 at lysine 27 (H3K27), with H3K27me2/3 being strongly associated with silenced genes. We demonstrate that EZH1 and EZH2, the two mutually exclusive catalytic subunits of PRC2, are differentially activated by various mechanisms. While both PRC2-EZH1 and PRC2-EZH2 are able to catalyze monomethylation, only PRC2-EZH2 is strongly activated by allosteric modulators and specific chromatin substrates to catalyze di-and trimethylation of H3K27. However, we also show that a PRC2 associated protein, AEBP2, can stimulate the activity of both complexes through a mechanism independent of and additive to allosteric activation. These results have strong implications regarding the cellular requirements for and accompanying adjustments in PRC2 activity, given the difference in the expression of EZH1 and EZH2 upon cellular differentiation.

scholarly journals Combinations of maternal-specific repressive epigenetic marks in the endosperm control seed dormancy

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Hikaru Sato ◽  
Juan Santos-González ◽  
Claudia Köhler
Keyword(s):  
Seed Dormancy ◽  
Histone H3 ◽  
Epigenetic Modifications ◽  
Polycomb Repressive Complex ◽  
Epigenetic Marks ◽  
Polycomb Repressive Complex 2 ◽  
Adaptive Trait ◽  
Control Seed ◽  
Histone 3

Polycomb Repressive Complex 2 (PRC2)-mediated trimethylation of histone H3 on lysine 27 (H3K27me3) and methylation of histone 3 on lysine 9 (H3K9me) are two repressive epigenetic modifications that are typically localized in distinct regions of the genome. For reasons unknown, however, they co-occur in some organisms and special tissue types. In this study, we show that maternal alleles marked by H3K27me3 in the Arabidopsis endosperm were targeted by the H3K27me3 demethylase REF6 and became activated during germination. In contrast, maternal alleles marked by H3K27me3, H3K9me2, and CHG methylation (CHGm) are likely to be protected from REF6 targeting and remained silenced. Our study unveils that combinations of different repressive epigenetic modifications time a key adaptive trait by modulating access of REF6.

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