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 Gene Silencing Triggers Polycomb Repressive Complex 2 Recruitment to CpG Islands Genome Wide

2014 ◽  
Vol 55 (3) ◽  
pp. 347-360 ◽  
Author(s):  
Eva Madi Riising ◽  
Itys Comet ◽  
Benjamin Leblanc ◽  
Xudong Wu ◽  
Jens Vilstrup Johansen ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Cpg Islands ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2 ◽  
Genome Wide

scholarly journals Bending and looping of long DNA by Polycomb repressive complex 2 revealed by AFM imaging in liquid

2020 ◽  
Vol 48 (6) ◽  
pp. 2969-2981 ◽  
Author(s):  
Patrick R Heenan ◽  
Xueyin Wang ◽  
Anne R Gooding ◽  
Thomas R Cech ◽  
Thomas T Perkins
Keyword(s):  
Gene Silencing ◽  
Single Molecule ◽  
Molecular Mechanisms ◽  
Cpg Island ◽  
Specific Binding ◽  
Gc Content ◽  
Polycomb Repressive Complex ◽  
Apparent Dissociation Constant ◽  
Polycomb Repressive Complex 2 ◽  
Epigenetic Gene Silencing

Abstract Polycomb repressive complex 2 (PRC2) is a histone methyltransferase that methylates histone H3 at Lysine 27. PRC2 is critical for epigenetic gene silencing, cellular differentiation and the formation of facultative heterochromatin. It can also promote or inhibit oncogenesis. Despite this importance, the molecular mechanisms by which PRC2 compacts chromatin are relatively understudied. Here, we visualized the binding of PRC2 to naked DNA in liquid at the single-molecule level using atomic force microscopy. Analysis of the resulting images showed PRC2, consisting of five subunits (EZH2, EED, SUZ12, AEBP2 and RBBP4), bound to a 2.5-kb DNA with an apparent dissociation constant ($K_{\rm{D}}^{{\rm{app}}}$) of 150 ± 12 nM. PRC2 did not show sequence-specific binding to a region of high GC content (76%) derived from a CpG island embedded in such a long DNA substrate. At higher concentrations, PRC2 compacted DNA by forming DNA loops typically anchored by two or more PRC2 molecules. Additionally, PRC2 binding led to a 3-fold increase in the local bending of DNA’s helical backbone without evidence of DNA wrapping around the protein. We suggest that the bending and looping of DNA by PRC2, independent of PRC2’s methylation activity, may contribute to heterochromatin formation and therefore epigenetic gene silencing.

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 Capturing the onset of PRC2-mediated repressive domain formation

2018 ◽  
Author(s):  
Ozgur Oksuz ◽  
Varun Narendra ◽  
Chul-Hwan Lee ◽  
Nicolas Descostes ◽  
Gary LeRoy ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Long Range ◽  
De Novo ◽  
Histone H3 ◽  
Domain Formation ◽  
Polycomb Repressive Complex 2 ◽  
Nucleation Sites ◽  
In Cis ◽  
Step Mechanism

SummaryPolycomb repressive complex 2 (PRC2) maintains gene silencing by catalyzing methylation of histone H3 at lysine 27 (H3K27me2/3) within chromatin. By designing a system whereby PRC2-mediated repressive domains were collapsed and then reconstructed in an inducible fashion in vivo, a two-step mechanism of H3K27me2/3 domain formation became evident. First, PRC2 is stably recruited by the actions of JARID2 and MTF2 to a limited number of spatially interacting “nucleation sites”, creating H3K27me3-forming polycomb foci within the nucleus. Second, PRC2 is allosterically activated via its binding to H3K27me3 and rapidly spreads H3K27me2/3 both in cis and in far-cis via long-range contacts. As PRC2 proceeds further from the nucleation sites, its stability on chromatin decreases such that domains of H3K27me3 remain proximal, and those of H3K27me2 distal, to the nucleation sites. This study demonstrates the principles of de novo establishment of PRC2-mediated repressive domains across the genome.

scholarly journals Downregulation of the Polycomb-Associated Methyltransferase Ezh2 during Maturation of Hippocampal Neurons Is Mediated by MicroRNAs Let-7 and miR-124

2020 ◽  
Vol 21 (22) ◽  
pp. 8472
Author(s):  
Laura Guajardo ◽  
Rodrigo Aguilar ◽  
Fernando J. Bustos ◽  
Gino Nardocci ◽  
Rodrigo A. Gutiérrez ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Hippocampal Neurons ◽  
Gene Sequence ◽  
Histone H3 ◽  
Catalytic Subunit ◽  
Maturation Process ◽  
Polycomb Repressive Complex 2 ◽  
Ezh2 Expression ◽  
Epigenetic Gene Silencing ◽  
Mature Neurons

Ezh2 is a catalytic subunit of the polycomb repressive complex 2 (PRC2) which mediates epigenetic gene silencing through depositing the mark histone H3 lysine 27 trimethylation (H3K27me3) at target genomic sequences. Previous studies have demonstrated that Enhancer of Zeste Homolog 2 (Ezh2) was differentially expressed during maturation of hippocampal neurons; in immature neurons, Ezh2 was abundantly expressed, whereas in mature neurons the expression Ezh2 was significantly reduced. Here, we report that Ezh2 is downregulated by microRNAs (miRs) that are expressed during the hippocampal maturation process. We show that, in mature hippocampal neurons, lethal-7 (let-7) and microRNA-124 (miR-124) are robustly expressed and can target cognate motifs at the 3′-UTR of the Ezh2 gene sequence to downregulate Ezh2 expression. Together, these data demonstrate that the PRC2 repressive activity during hippocampal maturation is controlled through a post-transcriptional mechanism that mediates Ezh2 downregulation in mature neurons.

scholarly journals Ikaros mediates gene silencing in T cells through Polycomb repressive complex 2

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Attila Oravecz ◽  
Apostol Apostolov ◽  
Katarzyna Polak ◽  
Bernard Jost ◽  
Stéphanie Le Gras ◽  
...  
Keyword(s):  
T Cells ◽  
Gene Silencing ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2

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.

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