Trends in Genetics
ReviewPolycomb Gene Silencing Mechanisms: PRC2 Chromatin Targeting, H3K27me3 'Readout', and Phase Separation-Based Compaction
Introduction
Pioneering studies on the genetics of Drosophila led to the discovery of the multi-subunit Polycomb repressive complexes, PRC2 and PRC1. Polycomb proteins EZH2/1, EED, SUZ12, and RBBP4/7 (Table 1) jointly establish a PRC2 'core' (Box 1) which exhibits an exquisite molecular architecture that permits functional modulation. This topic has been reviewed elsewhere [1., 2., 3., 4., 5.]; our aim here is to overview recent advances in understanding PRC-mediated (epi)genomic and transcriptomic regulation at the interface of chromatin, RNA, and regulatory machineries. In the following we focus on (i) modulation of core PRC2 enzymatic activity, (ii) chromatin targeting and spreading of PRC2 versus its eviction and functional restriction, and (iii) Polycomb-mediated gene-silencing mechanisms, with a focus on effectors for H3K27me3, a PRC2-catalyzed histone post-translational modification (PTM).
Section snippets
Regulation of Core PRC2 Activity
The catalytic function of PRC2 is subject to multilevel regulation (Figure 1A) by conformational changes (such as allosteric activation, see Glossary), competitive inhibition, and influences from the chromatin environment.
De Novo Recruitment and Spreading of PRC2, versus Its Eviction and Polycomb Domain Restriction
PRC proteins are markedly dynamic in cells, and the majority rapidly diffuse throughout the nucleus [37,38]. It is widely held (Figure 2A) that de novo recruitment of PRC2 establishes initial H3K27me2/3 at 'nucleation' sites, followed by spreading of PRC2 and H3K27me3. Studies have also uncovered both stimulatory and antagonizing factors that affect PRC2 binding/residence on chromatin and its eviction or functional restriction. In contrast to Polycomb response elements (PREs), defined in
Molecular Underpinnings of Polycomb-Mediated Gene Silencing
Since the discovery that Polycomb factors are repressors of Hox expression in Drosophila, the field has speculated about the underlying mechanisms. Recent studies have unveiled the multilevel involvement of PRC2 and its enzymatic product (H3K27me3) in the recruitment of readers/effectors (Figure 2A, bottom/left; and Figure 3A) that comprise distinct classes that may mediate gene silencing via different molecular mechanisms. We also touch on gene-silencing mechanisms that are independent of
Concluding Remarks and Future Perspectives
Recent understanding of PRC2 architecture, its chromatin recruitment versus eviction, and Polycomb gene-silencing mechanisms, has greatly changed current views regarding how PRC2 exerts its (epi)genome- and transcriptome-regulatory effects. However, several key questions remain to be addressed (see Outstanding Questions).
First, the dissection of the roles of individual PRC2/1 subcomplexes/cofactors was mainly performed with mESCs [27,40,41,47]. Although this cell model has many advantages, the
Declaration of Interests
No interests are declared.
Glossary
- Allosteric activation
- this takes place when a modulator binds to a regulatory site (other than the active site) of an enzyme and activates/enhances enzyme function; this often involves a conformational change of the protein.
- Bivalent domain genes
- genes that harbor both active and repressive histone modifications (usually H3K4me3 and H3K27me3).
- Competitive inhibition
- inhibition of a pathway by competition for binding; for example, blockade of substrate binding by a non-substrate competitor.
- CpG island
References (143)
Genome regulation by Polycomb and Trithorax: 70 years and counting
Cell
(2017)The complexity of PRC2 subcomplexes
Trends Cell Biol.
(2019)Polycomb repressive complex 2 in an autoinhibited state
J. Biol. Chem.
(2017)Structural basis of EZH2 recognition by EED
Structure
(2007)Jarid2 methylation via the PRC2 complex regulates H3K27me3 deposition during cell differentiation
Mol. Cell
(2015)Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms
Mol. Cell
(2008)Histone methylation by PRC2 is inhibited by active chromatin marks
Mol. Cell
(2011)An evolutionary conserved epigenetic mark of Polycomb response elements implemented by Trx/MLL/COMPASS
Mol. Cell
(2016)Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation
Cell
(2014)R-loops enhance Polycomb repression at a subset of developmental regulator genes
Mol. Cell
(2019)
EPOP functionally links Elongin and Polycomb in pluripotent stem cells
Mol. Cell
A high-density map for navigating the human Polycomb complexome
Cell Rep.
PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation
Blood
RYBP–PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3
Cell
The polycomb group protein L3mbtl2 assembles an atypical PRC1-family complex that is essential in pluripotent stem cells and early development
Cell Stem Cell
Combinatorial control of recruitment of a variant PRC1.6 complex in embryonic stem cells
Cell Rep.
Establishment of histone H3 methylation on the inactive X chromosome requires transient recruitment of Eed–Enx1 polycomb group complexes
Dev. Cell
Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs
Cell
Interactions between JARID2 and noncoding RNAs regulate PRC2 recruitment to chromatin
Mol. Cell
Jarid2 is implicated in the initial Xist-induced targeting of PRC2 to the inactive X chromosome
Mol. Cell
Gene silencing triggers polycomb repressive complex 2 recruitment to CpG islands genome wide
Mol. Cell
Ring1B compacts chromatin structure and represses gene expression independent of histone ubiquitination
Mol. Cell
SAM domain polymerization links subnuclear clustering of PRC1 to gene silencing
Dev. Cell
PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes
Mol. Cell
Targeting Polycomb systems to regulate gene expression: modifications to a complex story
Nat. Rev. Mol. Cell Biol.
PRC2 is high maintenance
Genes Dev.
Engaging chromatin: PRC2 structure meets function
Br. J. Cancer
Structure of the catalytic domain of EZH2 reveals conformational plasticity in cofactor and substrate binding sites and explains oncogenic mutations
PLoS One
Structural context of disease-associated mutations and putative mechanism of autoinhibition revealed by X-ray crystallographic analysis of the EZH2-SET domain
PLoS One
Identification of a novel, recurrent MBTD1–CXorf67 fusion in low-grade endometrial stromal sarcoma
Int. J. Cancer
PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism
Nat. Commun.
EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma
Neuro-Oncology
CATACOMB: an endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism
Sci. Adv.
H3 K27M and EZHIP impede H3K27-methylation spreading by inhibiting allosterically stimulated PRC2
Mol. Cell
Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma
Nature
Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma
Science
Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma
Sci. Adv.
Total kinetic analysis reveals how combinatorial methylation patterns are established on lysines 27 and 36 of histone H3
Proc. Natl. Acad. Sci. U. S. A.
Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2
Science
Role of the polycomb protein EED in the propagation of repressive histone marks
Nature
Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2
Nat. Commun.
Propagation of trimethylated H3K27 regulated by polycomb protein EED is required for embryogenesis, hematopoietic maintenance, and tumor suppression
Proc. Natl. Acad. Sci. U. S. A.
Distinct stimulatory mechanisms regulate the catalytic activity of Polycomb Repressive Complex 2
Mol. Cell
Allosteric activation dictates PRC2 activity independent of its recruitment to chromatin
Mol. Cell
Convergent evolution between PALI1 and JARID2 for the allosteric activation of PRC2
BioRxiv
Capturing the onset of PRC2-mediated repressive domain formation
Mol. Cell
Accurate H3K27 methylation can be established de novo by SUZ12-directed PRC2
Nat. Struct. Mol. Biol.
Nucleation and propagation of heterochromatin by the histone methyltransferase PRC2: geometric constraints and impact of the regulatory subunit JARID2
J. Am. Chem. Soc.
Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes
Nat. Struct. Mol. Biol.
Dissecting the role of H3K27 acetylation and methylation in PRC2 mediated control of cellular identity
Nat. Commun.
Cited by (60)
Review: Targeting EZH2 in neuroblastoma
2023, Cancer Treatment ReviewsIn-depth understanding of higher-order genome architecture in orphan cancer
2023, Biochimica et Biophysica Acta - Reviews on CancerThe molecular basis of heterochromatin assembly and epigenetic inheritance
2023, Molecular Cell