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

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.

Download Full-text

Faculty Opinions recommendation of The histone H3 lysine 9 methyltransferases G9a and GLP regulate polycomb repressive complex 2-mediated gene silencing.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718228225.793499412 ◽

2014 ◽

Author(s):

Anne Ferguson-Smith ◽

Celia Delahaye

Keyword(s):

Gene Silencing ◽

Histone H3 ◽

Polycomb Repressive Complex ◽

Polycomb Repressive Complex 2

Download Full-text

The Roles of the Histone Protein Modifier EZH2 in the Uterus and Placenta

Epigenomes ◽

10.3390/epigenomes4030020 ◽

2020 ◽

Vol 4 (3) ◽

pp. 20

Author(s):

Ana M. Mesa ◽

Cheryl S. Rosenfeld ◽

Geetu Tuteja ◽

Theresa I. Medrano ◽

Paul S. Cooke

Keyword(s):

Critical Role ◽

Histone H3 ◽

Gene Promoter ◽

Epigenetic Changes ◽

Promoter Regions ◽

Polycomb Repressive Complex 2 ◽

Gene Sets ◽

Ezh2 Expression ◽

And Function ◽

Transcription Enhancer

Epigenetic modifications regulate normal physiological, as well as pathological processes in various organs, including the uterus and placenta. Both organs undergo dramatic and rapid restructuring that depends upon precise orchestration of events. Epigenetic changes that alter transcription and translation of gene-sets regulate such responses. Histone modifications alter the chromatin structure, thereby affecting transcription factor access to gene promoter regions. Binding of histones to DNA is regulated by addition or removal of subunit methyl and other groups, which can inhibit or stimulate transcription. Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3) and subsequently suppresses transcription of genes bound by such histones. Uterine EZH2 expression exerts a critical role in development and function of this organ with deletion of this gene resulting in uterine hyperplasia and expression of cancer-associated transcripts. Elucidating the roles of EZH2 in uterus and placenta is essential as EZH2 dysregulation is associated with several uterine and placental pathologies. Herein, we discuss EZH2 functions in uterus and placenta, emphasizing its physiological and pathological importance.

Download Full-text

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

Nucleic Acids Research ◽

10.1093/nar/gkaa073 ◽

2020 ◽

Vol 48 (6) ◽

pp. 2969-2981 ◽

Cited By ~ 2

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.

Download Full-text

Capturing the onset of PRC2-mediated repressive domain formation

10.1101/272989 ◽

2018 ◽

Cited By ~ 2

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.

Download Full-text

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

Molecular Cell ◽

10.1016/j.molcel.2013.12.005 ◽

2014 ◽

Vol 53 (2) ◽

pp. 277-289 ◽

Cited By ~ 116

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

Download Full-text

EARLY IN SHORT DAYS 7(ESD7) encodes the catalytic subunit of DNA polymerase epsilon and is required for flowering repression through a mechanism involving epigenetic gene silencing

The Plant Journal ◽

10.1111/j.1365-313x.2009.04093.x ◽

2010 ◽

Vol 61 (4) ◽

pp. 623-636 ◽

Cited By ~ 41

Author(s):

Iván del Olmo ◽

Leticia López-González ◽

Maria M. Martín-Trillo ◽

José M. Martínez-Zapater ◽

Manuel Piñeiro ◽

...

Keyword(s):

Gene Silencing ◽

Dna Polymerase ◽

Catalytic Subunit ◽

Dna Polymerase Epsilon ◽

Epigenetic Gene Silencing ◽

Polymerase Epsilon ◽

Short Days

Download Full-text

Structures of monomeric and dimeric PRC2:EZH1 reveal flexible modules involved in chromatin compaction

Nature Communications ◽

10.1038/s41467-020-20775-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Daniel Grau ◽

Yixiao Zhang ◽

Chul-Hwan Lee ◽

Marco Valencia-Sánchez ◽

Jenny Zhang ◽

...

Keyword(s):

Gene Silencing ◽

Conformational Change ◽

Conformational Flexibility ◽

Catalytic Subunit ◽

Biological Functions ◽

Polycomb Repressive Complex ◽

Chromatin Compaction ◽

Polycomb Repressive Complex 2 ◽

Selective Incorporation ◽

Nucleosome Binding

AbstractPolycomb repressive complex 2 (PRC2) is a histone methyltransferase critical for maintaining gene silencing during eukaryotic development. In mammals, PRC2 activity is regulated in part by the selective incorporation of one of two paralogs of the catalytic subunit, EZH1 or EZH2. Each of these enzymes has specialized biological functions that may be partially explained by differences in the multivalent interactions they mediate with chromatin. Here, we present two cryo-EM structures of PRC2:EZH1, one as a monomer and a second one as a dimer bound to a nucleosome. When bound to nucleosome substrate, the PRC2:EZH1 dimer undergoes a dramatic conformational change. We demonstrate that mutation of a divergent EZH1/2 loop abrogates the nucleosome-binding and methyltransferase activities of PRC2:EZH1. Finally, we show that PRC2:EZH1 dimers are more effective than monomers at promoting chromatin compaction, and the divergent EZH1/2 loop is essential for this function, thereby tying together the methyltransferase, nucleosome-binding, and chromatin-compaction activities of PRC2:EZH1. We speculate that the conformational flexibility and the ability to dimerize enable PRC2 to act on the varied chromatin substrates it encounters in the cell.

Download Full-text