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PRC2

Polycomb repressive complex 2 (PRC2) is an evolutionarily conserved, multi-subunit epigenetic regulator that functions as a histone methyltransferase, primarily catalyzing the trimethylation of lysine 27 on histone H3 (H3K27me3) to mediate transcriptional repression of developmental genes across eukaryotes.^[1]^[2] The core composition of PRC2 includes the catalytic subunit EZH2 (or its paralog EZH1 in mammals), the regulatory subunit EED, the scaffold protein SUZ12, and the histone-binding protein RBBP4 or RBBP7, which together form a stable complex essential for its enzymatic activity.^[1] Accessory subunits such as JARID2, AEBP2, or polycomb-like (PCL) proteins further diversify PRC2 into subcomplexes like PRC2.1 and PRC2.2, enhancing its chromatin targeting and stimulation in specific contexts.^[1] Structurally, PRC2 adopts a compact, four-lobed architecture that facilitates allosteric activation, where EED recognizes preexisting H3K27me3 marks to propagate silencing through a positive feedback loop.^[1] In terms of function, PRC2 plays a pivotal role in maintaining cellular identity and differentiation by silencing Hox genes and other developmental loci, with its activity modulated by interactions with noncoding RNAs, DNA elements, and opposing histone marks like H3K4me3 or H3K36me3.^[2] Across species, from unicellular algae to multicellular plants and animals, PRC2 represses transposable elements, controls flowering and embryogenesis in plants, and regulates stem cell pluripotency in mammals, underscoring its ancient origins near the last eukaryotic common ancestor.^[2] Dysregulation of PRC2, often through mutations in EZH2 (such as gain-of-function Y641 variants), is implicated in various cancers including lymphomas and myeloid malignancies, where altered H3K27me3 levels drive aberrant gene expression and tumorigenesis.^[1] Ongoing research highlights PRC2's therapeutic potential, with inhibitors targeting its catalytic activity, such as tazemetostat (FDA-approved in 2020 for EZH2-mutant follicular lymphoma) and valemetostat (approved in Japan in 2022 and 2024 for T-cell lymphomas), showing promise in treating PRC2-dependent tumors.^[1]^[3]^[4]

Discovery and nomenclature

Historical discovery

The discovery of the Polycomb group (PcG) genes originated in the 1940s and 1950s through genetic screens in Drosophila melanogaster aimed at identifying mutations affecting homeotic gene expression, which controls segmental identity along the body axis. In 1947, Pamela Lewis isolated the Polycomb (Pc) mutation, which caused homeotic transformations by leading to ectopic expression of Hox genes in anterior segments, mimicking a posterior fate. This phenotype indicated that Pc normally represses Hox genes after their initial activation during embryogenesis. Edward B. Lewis expanded on this in 1978, describing the bithorax complex and proposing that Pc and related genes act as repressors to maintain stable, heritable silencing of developmental regulators, forming the foundation of PcG function. Biochemical studies in the early 2000s revealed that PcG proteins assemble into multiprotein complexes with enzymatic activity. In Drosophila, purification from embryos identified the Enhancer of Zeste (E(z))-Esc complex, now known as PRC2, which possesses histone methyltransferase (HMT) activity specific for lysine 27 on histone H3 (H3K27). Key experiments, including in vitro methylation assays on synthetic peptides and nucleosomes, demonstrated that this activity correlates with Hox gene silencing, as E(z) mutants lose H3K27 methylation at Polycomb target genes like Ultrabithorax and exhibit derepression. Parallel work in mammals identified a homologous complex containing EZH2 (the E(z) ortholog), EED, and SUZ12 through immunoprecipitation and mass spectrometry from HeLa cell extracts, confirming its HMT activity for H3K27me3, the trimethylated form linked to transcriptional repression. These 2002 studies established PRC2 as the enzymatic core of PcG silencing.^[5]^[6] Genetic validation in mice underscored PRC2's essential role in mammalian development. In 2001, targeted disruption of the Ezh2 gene produced homozygous null embryos that arrested at embryonic day 7.5 (E7.5) to E8.5, with defects in gastrulation and widespread Hox derepression due to loss of H3K27me3, mirroring Drosophila phenotypes. Further milestones included the 2007 crystal structure of the EED-EZH2 interaction domain, revealing how EED stabilizes EZH2's catalytic SET domain via a WD40 β-propeller fold, enabling allosteric regulation. By 2010, genomic surveys confirmed PRC2's evolutionary conservation beyond animals, identifying homologs in plants (e.g., CURLY LEAF ortholog of EZH2) and certain fungi (e.g., Neurospora crassa), where it similarly deposits H3K27me3 to repress developmental genes, highlighting its ancient origin in eukaryotes. More recent studies (as of 2023) have traced PRC2's origins further back, identifying functional homologs in unicellular red algae where it represses transposable elements, suggesting an even earlier eukaryotic emergence.^[7]

Nomenclature across species

The nomenclature of Polycomb Repressive Complex 2 (PRC2) components reflects their discovery through genetic screens in model organisms and subsequent identification of homologs across eukaryotes, emphasizing the complex's evolutionary conservation in mediating gene repression via histone H3 lysine 27 (H3K27) methylation.^[2] In humans and other mammals, the core PRC2 is composed of EZH2 (Enhancer of Zeste Homolog 2), the primary catalytic subunit; SUZ12 (Suppressor of Zeste 12); EED (Embryonic Ectoderm Development); and RbAp46/48 (Retinoblastoma-associated proteins 46/48, also known as RBBP7/RBBP4).^[2] These names derive from homology to Drosophila proteins and functional studies linking them to developmental repression.^[2] In Drosophila melanogaster, the foundational model for Polycomb group proteins, PRC2 homologs are named E(z) (Enhancer of Zeste) for the EZH2 ortholog, Su(z)12 (Suppressor of Zeste 12) for SUZ12, Esc (Extra Sex Combs) for EED, and Nurf55 (Nucleosome Remodeling Factor 55, a p55 homolog) for RbAp46/48.^[2] Plant PRC2 nomenclature, exemplified in Arabidopsis thaliana, features multiple paralogs reflecting subfunctionalization: CLF (CURLY LEAF) and SWN (SWINGER) as primary EZH2 homologs alongside MEA (MEDEA); VRN2 (VERNALIZATION 2), EMF2 (EMBRYONIC FLOWER 2), and FIS2 (FERTILIZATION INDEPENDENT SEED 2) as SUZ12 homologs; and FIE (FERTILIZATION INDEPENDENT ENDOSPERM) as the EED homolog.^[8] These names stem from mutant phenotypes affecting leaf curling, flowering timing, and seed development.^[8] Alternative names and isoforms include EZH1 (Enhancer of Zeste Homolog 1), a paralog of EZH2 with reduced catalytic activity that can form non-canonical PRC2 complexes.^[9] The overarching term "Polycomb Repressive Complex 2" was coined around 2001 to distinguish this H3K27 methyltransferase from the related PRC1, based on biochemical purification and genetic studies in mammals and flies.^[2] PRC2-like complexes exhibit conservation in other lineages, such as fungi where Neurospora crassa uses SET-7 (EZH2 homolog) and lacks a full SUZ12 equivalent in some species like Saccharomyces cerevisiae; and nematodes like Caenorhabditis elegans, where MES-2 (EZH2 homolog), MES-3 (SUZ12 substitute), MES-6 (EED homolog), and MES-4 contribute to a variant complex essential for germline silencing.^[2]

Molecular composition

Core subunits

The core of the Polycomb Repressive Complex 2 (PRC2) consists of four essential subunits: enhancer of zeste homolog 2 (EZH2) or its paralog EZH1, suppressor of zeste 12 (SUZ12), embryonic ectoderm development (EED), and retinoblastoma-binding protein 4 or 7 (RBBP4/7, also known as RbAp46/48).^[10] These subunits form the minimal functional unit required for basal histone methyltransferase activity across eukaryotes, with the complex assembling as a canonical 1:1:1:1 heterotetramer that has a molecular weight of approximately 200-250 kDa.^[11]^[12] EZH2 serves as the catalytic subunit of PRC2, containing a SET domain that confers histone-lysine N-methyltransferase activity, primarily targeting lysine 27 on histone H3 (H3K27).^[10] In humans, EZH2 is a 746-amino-acid protein that binds S-adenosylmethionine (SAM) as the methyl donor and histone substrates to facilitate mono-, di-, and trimethylation.^[13] Its paralog EZH1 can substitute for EZH2 in the core complex, forming similar heterotetramers but with distinct enzymatic properties; EZH2 predominates in proliferating cells to drive rapid H3K27 methylation, whereas EZH1 maintains repressive chromatin marks in non-dividing or differentiated cells.^[9] This isoform redundancy ensures PRC2 functionality across cell states, though EZH2-containing complexes exhibit higher catalytic efficiency on nucleosomal substrates.^[14] SUZ12 acts as a zinc finger-containing scaffold subunit that is indispensable for PRC2 assembly and stability, directly interacting with EZH2 to promote its incorporation into the complex.^[15] Without SUZ12, EZH2 levels diminish, and the complex fails to form productively, underscoring its role in coordinating subunit interactions.^[10] EED, a WD40 repeat protein, functions as a histone reader and allosteric regulator within PRC2, recognizing trimethylated H3K27 (H3K27me3) through a conserved aromatic cage in its beta-propeller domain to stimulate methyltransferase activity.^[16] This binding propagates H3K27me3 marks in a feed-forward manner, enhancing complex recruitment to chromatin.^[17] RBBP4 and RBBP7 (RbAp46/48) are interchangeable histone chaperones featuring seven WD40 blades that facilitate PRC2's interaction with nucleosomes by binding the histone H3-H4 dimer.^[18] These subunits contribute to substrate presentation for methylation, though they are not strictly required for core assembly in vitro.^[1]

Accessory proteins

Accessory proteins associate with the core PRC2 complex to modulate its recruitment, stability, and enzymatic activity in a context-dependent manner, forming distinct subcomplexes known as PRC2.1 and PRC2.2. These non-core components are not essential for basal in vitro methyltransferase activity but enhance specificity toward chromatin targets and fine-tune catalysis in vivo. Binding primarily occurs through interactions with the core subunits SUZ12 and EED, with SUZ12 serving as a central platform via its distinct structural domains, such as the ZnB-Zn and C2 regions.^[1]^[19] The PRC2.2 subcomplex incorporates JARID2 and AEBP2. JARID2 binds the SUZ12 ZnB-Zn domain and recruits PRC2 to developmental loci by recognizing GC-rich DNA sequences and nucleosomes bearing H2AK119ub1 via its UIM domain, facilitating targeting during embryogenesis. It inhibits PRC2's basal H3K27 methyltransferase activity while enabling allosteric stimulation upon engagement with chromatin cues, such as H2AK119ub1, which displaces inhibitory conformations to promote methylation. AEBP2, a zinc finger protein, interacts with the SUZ12 C2 domain and stimulates H3K27 methylation on nucleosomes by enhancing PRC2's chromatin affinity through its KRAB-associated motif and recognition of DNA motifs like CTT(N)_15–23cagGCC, thereby increasing catalytic efficiency.^[1]^[20]^[19] In contrast, the PRC2.1 subcomplex includes one of the Polycomb-like (PCL) proteins—PHF1, MTF2, or PHF19—often alongside EPOP or PALI1/2. These PCL proteins tether PRC2 to regions marked by H3K36me3 through their Tudor domains, which selectively recognize this active histone modification, while their extended homology (EH) domains bind unmethylated CpG islands to direct recruitment during lineage specification. MTF2 predominates in embryonic stem cells for repression at developmental genes, PHF1 enhances H3K27me3 deposition at CGG-rich motifs, and PHF19 antagonizes MTF2 at select loci while recruiting H3K36 demethylases. EPOP binds the SUZ12 ZnB-Zn domain and associates with PRC2 in embryonic stem cells, linking it to the Elongin BC complex to support low-level transcription at poised bivalent genes marked by H3K27me3.^[1]^[21]30663-3) Species-specific variations influence accessory protein composition; for instance, JARID2 is conserved across vertebrates and invertebrates including Drosophila melanogaster, where it associates with PRC2 for targeting, whereas PCL proteins exhibit expanded roles and diversity in mammals.^[22] Assembly dynamics involve competitive binding at SUZ12 sites, allowing subcomplex interconversion based on cellular context, such as differentiation stages, with JARID2 and PCL proteins showing reciprocal occupancy changes upon depletion.^[23]^[24]

Structural features

Overall architecture

The Polycomb repressive complex 2 (PRC2) core is composed of four subunits—EZH2 (or EZH1), SUZ12, EED, and RbAp46/48—forming a heterotetrameric assembly essential for its chromatin-modifying function. High-resolution cryo-electron microscopy (cryo-EM) structures, resolved between 2017 and 2020, reveal this core as a compact, two-lobed scaffold approximately 270 kDa in molecular weight, with the upper catalytic lobe encompassing the EZH2 SET domain, EED, and the C-terminal VEFS domain of SUZ12, and the lower regulatory lobe including the N-terminal regions of SUZ12 and RbAp46/48.^[25]^[26] A representative structure of the human PRC2 core in complex with the cofactor JARID2 achieves 3.5 Å resolution, highlighting an asymmetric arrangement where the core subunits integrate to form a stable platform for substrate recognition.^[25] Key inter-subunit interfaces stabilize this architecture. The SUZ12 VEFS domain engages EZH2 through α-helical extensions and zinc finger motifs, anchoring the catalytic lobe and promoting EZH2's stimulatory response motif (SRM) positioning.^[25] EED interacts with SUZ12 via an extended β-sheet, ensuring structural integrity across the lobes, while RbAp46 binds the C-terminal extension of EZH2, facilitating allosteric communication within the complex.^[25] These interfaces create a modular scaffold that accommodates accessory proteins like JARID2 or AEBP2 without disrupting the core tetramer.^[25] PRC2 exhibits dynamic conformational states modulated by histone marks. In the inactive basal state, the complex adopts an open configuration with flexible elements allowing substrate access, whereas binding of H3K27me3 to EED's aromatic cage induces a closed, active state that rigidifies the SRM and enhances catalysis.^[25]^[1] The overall shape is elongated, spanning about 15-16 nm in length with a thickness of ~7 nm, featuring flexible tails that enable nucleosome engagement while maintaining compactness for chromatin targeting.^[27] Subsequent cryo-EM structures from 2021 to 2025, achieving resolutions as low as 3.3 Å, have further elucidated regulatory interactions, such as inhibition by G-quadruplex RNAs and reduced engagement with H3K36me3-marked nucleosomes.^[28]^[29] This architecture is evolutionarily conserved across eukaryotes, with similar heterotetrameric cores observed in Drosophila melanogaster and plants, though plant PRC2 subunits like VRN2 (SUZ12 homolog) include species-specific N-terminal extensions for developmental adaptation.^[30]^[2] In Drosophila, the core subunits Esc (EED), Su(z)12, and E(z) (EZH2) form analogous interfaces, underscoring the complex's ancient role in gene repression.^[30]

Catalytic domain

The catalytic domain of PRC2 resides within the C-terminal SET domain of the EZH2 subunit, spanning approximately amino acids 631 to 746 and characterized by a split architecture consisting of Pre-SET, SET, and Post-SET regions.^[31] The Pre-SET region is a cysteine-rich domain also known as the CXC domain, which coordinates zinc ions essential for structural stability, while the core SET region forms the methyltransferase active site, and the Post-SET region contributes to completing the lysine access channel for substrate binding.^[31]^[32] This canonical SET domain features a SAM-binding pocket lined by conserved residues, including tyrosine 728 (Tyr728) and aspartic acid residues such as Asp652 and Asp659, which facilitate cofactor binding and catalysis through hydrogen bonding and hydrophobic interactions.^[33] Substrate recognition occurs via a basic pocket in the EZH2 SET domain that accommodates the N-terminal tail of histone H3, specifically residues 18 to 32, positioning lysine 27 (K27) for methylation. Specificity for unmethylated K27 is achieved through a hydrophobic groove adjacent to the active site, which sterically accommodates the unmodified lysine side chain while excluding methylated forms, thereby ensuring sequential mono-, di-, and trimethylation without interference from prior modifications. For cofactor interactions, S-adenosylmethionine (SAM) binds in the pocket to donate the methyl group, producing S-adenosylhomocysteine (SAH) as a byproduct; expulsion of SAH is mediated by conformational rearrangements in the Post-SET domain and adjacent loops, preventing product inhibition and allowing catalytic cycling. Additionally, a WD loop in EZH2 inserts into the WD40 repeat domain of the RbAp46/48 subunit, stabilizing the active conformation and stimulating methyltransferase activity through allosteric enhancement of substrate access.^[34] Inhibitor binding often targets allosteric pockets within or adjacent to the SET domain, such as the extended SAM-competitive site exploited by tazemetostat, which occupies a cleft involving an alpha-helix (residues around 640-650) to block cofactor and substrate entry, thereby inhibiting H3K27 methylation with high selectivity for EZH2-containing PRC2.^[35] In comparison to EZH2, the paralogous EZH1 exhibits lower intrinsic methyltransferase activity in PRC2 complexes, attributed to sequence variations in and around its SET domain that reduce catalytic efficiency by approximately 20-fold on nucleosomal substrates. This structural difference underlies the complementary roles of EZH1- and EZH2-containing PRC2 in maintaining repressive chromatin marks under varying cellular conditions.^[36]

Enzymatic activity and mechanism

Histone H3K27 methylation

PRC2 functions as the primary histone methyltransferase responsible for depositing methyl groups onto lysine 27 of histone H3 (H3K27), utilizing S-adenosylmethionine (SAM) as the methyl donor to generate mono-, di-, and trimethylated forms denoted as H3K27me1, H3K27me2, and H3K27me3, respectively.^[37] The catalytic activity resides in the SET domain of the EZH2 (or EZH1) subunit, which sequentially transfers up to three methyl groups, releasing S-adenosylhomocysteine (SAH) as the byproduct with each addition.^[38] On nucleosomal substrates, PRC2 shows a marked preference for producing the trimethylated form H3K27me3, which accumulates as the dominant product due to processive methylation.^[19] The core biochemical reaction can be summarized for trimethylation as follows:

\text{H3K27} + 3 \text{SAM} \rightarrow \text{H3K27me3} + 3 \text{SAH}

This process begins with monomethylation of unmodified H3K27 and proceeds through dimethylated intermediates, with structural studies revealing that the H3 tail accesses the active site in a conformation that positions the ε-amino group of lysine 27 for nucleophilic attack on the SAM-bound methyl group.^[38] PRC2 displays intrinsically low basal methyltransferase activity toward H3K27, particularly on intact nucleosomes, where turnover rates are limited without regulatory inputs.^[39] This basal catalysis is enhanced several-fold through allosteric recognition of preexisting H3K27me3 by the EED subunit, which binds the mark via an aromatic cage and stimulates EZH2's active site for more efficient methylation.^[40] Substrate specificity of PRC2 is tightly regulated to target repressive chromatin domains. The complex efficiently methylates free histone H3 tails (e.g., residues 1–50) or mononucleosomes containing unmodified H3K27, with binding affinities in the sub-micromolar range for H3 peptides (K_D ≈ 0.8 μM).^[41] However, the presence of the active mark H3K4me3 on the same H3 tail (in cis) allosterically inhibits activity by engaging a distinct binding pocket, reducing the catalytic rate (k_cat) approximately 8-fold (from 2.53 min⁻¹ to 0.32 min⁻¹ on peptides) and the specificity constant (k_cat/K_M) by over 10-fold, thereby preventing ectopic methylation on transcriptionally active chromatin.^[41] This inhibition is specific to cis-configured marks and does not occur with trans nucleosomes bearing H3K4me3. Recent structural studies (as of 2024) have revealed that H3K4me3 and H3K36me3 inhibit PRC2 through distinct mechanisms: H3K4me3 binds an allosteric pocket similar to repressive marks but blocks activation, while H3K36me3 competes directly at the active site.^[29] Beyond histones, PRC2 exhibits minor activity toward select non-histone substrates in specific cellular contexts, such as monomethylation of the transcription factor GATA4 at lysine residues, which diminishes its DNA-binding affinity and transcriptional activation potential by impairing interactions with coactivators like p300. Such non-histone modifications represent a secondary facet of PRC2's enzymatic output, subordinate to its dominant role in H3K27 methylation.

Allosteric activation

The allosteric activation of PRC2 is primarily mediated by the binding of its product, histone H3 lysine 27 trimethylation (H3K27me3), to the WD40 domain of the EED subunit. This interaction occurs within EED's aromatic cage, a structural pocket formed by conserved aromatic residues (such as Phe97, Tyr148, and Tyr365) that engage the trimethylammonium group of H3K27me3 through π-cation interactions, stabilizing the complex and transmitting a signal to the catalytic SET domain of EZH2.^[40] This binding induces a conformational shift in PRC2, relieving autoinhibition and enhancing the methyltransferase activity toward unmodified H3K27 substrates. A key structural feature in this process is the stimulation-responsive motif (SRM) of EZH2, an autoinhibitory loop in the N-terminal region that occupies the substrate-binding cleft in the basal state of PRC2. Upon H3K27me3 engagement by EED, the SRM undergoes a dynamic rearrangement, transitioning from an extended loop to a structured α-helix that interacts with the EZH2 SET-I domain, thereby opening the active site for improved histone tail access and catalysis. Cryo-EM structures of PRC2 bound to H3K27me3 peptides or nucleosomes illustrate this loop displacement, showing the SRM moving away from the SET domain toward the EED interface, which facilitates inter-subunit communication and stabilizes the activated conformation. This allosteric mechanism establishes a positive feedback loop, where initial low-level H3K27 methylation events generate H3K27me3 marks that recruit additional PRC2 complexes, seeding further methylation and propagating repressive domains across chromatin. The accessory protein JARID2 enhances this amplification when trimethylated at lysine 116 (JARID2-K116me3), which binds the EED aromatic cage in a manner analogous to H3K27me3, promoting PRC2 recruitment and activity at target loci during early developmental stages.^[42] Biochemically, H3K27me3 binding dramatically boosts PRC2's catalytic efficiency, increasing the turnover number (k_cat) by approximately 300-fold and enabling processive di- and tri-methylation of H3K27 on the same nucleosome, which is critical for establishing stable epigenetic silencing.^[40] Without this activation, PRC2 exhibits basal activity insufficient for efficient mark propagation. Pathologically, disruptions to this allosteric pathway contribute to oncogenesis. For instance, the EED-I363M mutation, found in myeloid malignancies, impairs H3K27me3 binding to the EED aromatic cage, leading to loss of allosteric activation, reduced PRC2 activity, decreased global H3K27me3 levels, and associated disease progression.^[43]

Biological roles

In gene silencing and epigenetics

PRC2 plays a central role in establishing and maintaining transcriptional repression by targeting specific genomic elements and depositing the repressive histone modification H3K27me3. In mammalian cells, PRC2 is recruited to CpG islands, which are GC-rich DNA sequences often associated with gene promoters, through interactions with transcription factors such as YY1.^[44]^[45] Similarly, Polycomb Response Elements (PREs), analogous to those in Drosophila, facilitate PRC2 binding in mammals via sequence-specific DNA motifs and associated proteins.^[46] This targeted recruitment initiates local H3K27me3 deposition, which propagates to silence nearby genes.^[47] Once established, H3K27me3 recruits Polycomb Repressive Complex 1 (PRC1), which monoubiquitinates histone H2A at lysine 119 (H2AK119ub), promoting chromatin compaction and further reinforcing transcriptional silencing.^[48]^[49] This cooperative interplay between PRC2 and PRC1 creates a stable repressive chromatin environment that prevents unauthorized gene expression.^[50] In embryonic stem cells, PRC2 contributes to bivalent chromatin domains at promoters of developmental genes, where H3K27me3 coexists with the active mark H3K4me3 to maintain a poised state for rapid activation during differentiation.^[51] These domains balance repression and potential activation, ensuring lineage-appropriate gene expression upon cellular commitment.^[51] PRC2's silencing function exhibits epigenetic memory, enabling heritable repression across cell divisions through a self-reinforcing feedback loop: pre-existing H3K27me3 binds the EED subunit of PRC2, allosterically stimulating further methylation on adjacent nucleosomes. This mechanism sustains the repressive mark during DNA replication and mitosis, preserving gene silencing in daughter cells.^[52] Genome-wide chromatin immunoprecipitation studies in mammalian embryonic stem cells reveal PRC2 enrichment at approximately 2,000 loci, predominantly at developmental regulators including Hox gene clusters, underscoring its broad role in epigenetic control.^[53]

In embryonic development and stem cells

PRC2 plays a critical role in maintaining the pluripotency of embryonic stem cells (ESCs) by repressing genes associated with lineage commitment. In mouse ESCs, knockdown or knockout of the core PRC2 subunit Ezh2 leads to derepression of developmental regulators, resulting in loss of self-renewal and spontaneous differentiation into multiple lineages. For instance, Ezh2 represses neuronal lineage genes such as Neurod1, preventing premature neural differentiation and ensuring the undifferentiated state.^[54] This repressive function is mediated through H3K27me3 deposition at promoters of poised developmental genes, often in bivalent chromatin domains that balance repression with readiness for activation upon differentiation signals.^[51] In embryonic development, PRC2 is essential for proper Hox gene regulation, which governs anterior-posterior patterning. PRC2 silences posterior Hox genes in anterior regions of the embryo, restricting their expression to appropriate domains along the body axis. Disruption of PRC2 function, as seen in Ezh2 knockout mice, causes ectopic expression of posterior Hox genes, leading to homeotic transformations such as posteriorization of anterior structures; these mutants are embryonic lethal around E7.5 with severe patterning defects.^[55] Similarly, Eed-null chimeras exhibit rostral shifts in Hox expression boundaries, underscoring PRC2's role in stable Hox repression during gastrulation and somitogenesis.^[56] PRC2 also contributes to X-chromosome inactivation (XCI) in female embryos, a process that equalizes X-linked gene dosage. Upon Xist RNA coating of the future inactive X chromosome (Xi), PRC2 is recruited to initiate H3K27me3 enrichment across the Xi, promoting facultative heterochromatin formation and gene silencing. This PRC2-dependent modification is one of the earliest chromatin marks on the Xi during imprinted XCI in extraembryonic tissues and random XCI in the embryo proper. Beyond XCI, PRC2 participates in genomic imprinting by facilitating parent-of-origin-specific gene expression at select loci. The long non-coding RNA Kcnq1ot1, expressed from the paternal allele at the Kcnq1 domain on chromosome 7, recruits PRC2 components including Ezh2 and Suz12 to mediate silencing of neighboring maternally expressed genes in a lineage-specific manner, such as in placenta but not fetal liver.^[57] This interaction establishes H3K27me3 at imprinted promoters, contributing to the monoallelic repression required for normal embryonic growth.^[57] The activity of PRC2 exhibits temporal dynamics during the transition from naive pluripotency to differentiation. In naive pluripotent stem cells (PSCs), Ezh2 levels and associated H3K27me3 are elevated to maintain repression of differentiation genes, but these decrease as cells exit the naive state and commit to lineages.^[58] In differentiated and adult somatic cells, Ezh1 largely compensates for reduced Ezh2, sustaining lower but essential H3K27me3 levels for tissue homeostasis and preventing aberrant reactivation of developmental programs.^[59]

PRC2 in human disease

Role in cancer

PRC2, particularly through its catalytic subunit EZH2, exhibits oncogenic functions in various cancers via overexpression and gain-of-function mutations that enhance H3K27 trimethylation, leading to aberrant gene repression. In lymphomas and prostate cancer, somatic mutations such as Y641F in EZH2 increase the enzyme's preference for di- and tri-methylated H3K27 substrates, resulting in hyper-trimethylation and heightened repressive activity that drives tumorigenesis.^[60] This mutation is recurrent in follicular lymphoma and diffuse large B-cell lymphoma, where it cooperates with other genetic alterations to promote lymphomagenesis by altering chromatin structure and repressing tumor-suppressive pathways.^[61] Conversely, loss-of-function alterations in PRC2 components can also contribute to oncogenesis in certain contexts, notably in myelodysplastic syndromes (MDS). Mutations in ASXL1, a PRC2-associated factor, disrupt its interaction with the EED subunit, leading to PRC2 inactivation and reduced H3K27me3 levels, which impairs myeloid differentiation and promotes clonal expansion of malignant cells.^[62] These ASXL1 mutations occur in 10-30% of MDS cases and are associated with progression to acute myeloid leukemia through loss of PRC2-mediated gene repression.^[63] PRC2 dysregulation is prevalent across cancer types, with EZH2 upregulation observed frequently in solid tumors such as breast and bladder cancer, where it correlates with aggressive disease and poor prognosis.^[64] In B-cell lymphomas, EZH2 is essential for tumor maintenance, particularly in cases harboring activating mutations, underscoring its therapeutic vulnerability; tazemetostat, an EZH2 inhibitor, received FDA approval in 2020 for relapsed or refractory EZH2-mutant follicular lymphoma based on phase II trial data showing objective response rates of approximately 69%.^[65] Mechanistically, oncogenic PRC2 activity silences tumor suppressor genes, including CDKN2A (encoding p16INK4a and p14ARF), via H3K27me3 deposition at their promoters, thereby facilitating cell cycle deregulation and proliferation.^[64] Additionally, EZH2 promotes cancer metastasis by inducing epithelial-mesenchymal transition (EMT), downregulating epithelial markers like E-cadherin while upregulating mesenchymal factors such as vimentin, which enhances invasiveness in tumors like breast and pancreatic cancer.^[66] Therapeutic targeting of PRC2 has advanced with selective EZH2 inhibitors like GSK126, which potently blocks H3K27 methylation (IC50 ≈ 0.5-3 nM) and suppresses growth in EZH2-mutant lymphoma models by reactivating silenced genes. As of 2025, clinical trials have demonstrated good tolerability for EZH2 inhibitors in combination with PD-1 blockade, such as tazemetostat plus pembrolizumab in advanced solid tumors like head and neck squamous cell carcinoma (no dose-limiting toxicities, stable disease in 42% of patients), with preliminary antitumor responses observed in other trials including advanced urothelial carcinoma (ORR 21%). Ongoing studies are evaluating these combinations in lymphomas to enhance immune infiltration and overcome resistance.^[67]^[68] As of 2025, updated patents for EZH2 inhibitors highlight ongoing development for cancers and potential applications in non-cancerous conditions.^[69]

Involvement in other disorders

PRC2 dysregulation has been implicated in several non-oncogenic human disorders, particularly those involving developmental overgrowth and intellectual impairment. In Weaver syndrome, a rare overgrowth disorder characterized by tall stature, macrocephaly, and intellectual disability, germline heterozygous missense mutations in EZH2, such as p.Ala682Gly (A682G), act in a dominant-negative manner to impair PRC2's histone methyltransferase activity, leading to reduced H3K27me3 levels and disrupted gene silencing.^[70]^[71] These mutations, identified in multiple affected individuals, highlight EZH2's critical role in regulating somatic growth and neurodevelopment, with affected patients often exhibiting skeletal anomalies and developmental delays alongside the overgrowth phenotype.^[70] Beyond direct PRC2 component mutations, imbalances in opposing epigenetic marks can indirectly perturb PRC2 function in developmental syndromes. Kabuki syndrome type 1, a neurodevelopmental disorder featuring distinctive facial features, intellectual disability, and congenital anomalies, arises from loss-of-function mutations in KMT2D, which encodes a histone H3K4 methyltransferase. These mutations reduce H3K4me3 deposition, particularly at bivalent promoters marked by both H3K4me3 and H3K27me3, resulting in enhanced PRC2-mediated H3K27me3 and aberrant gene repression that contributes to the syndrome's developmental defects.^[72] This epigenetic imbalance underscores how disruptions in activating marks can amplify PRC2's repressive effects, leading to dysregulated expression of developmental genes.^[72] Neurological disorders, including features of autism spectrum disorder (ASD), have been linked to PRC2 haploinsufficiency through derepression of synaptic genes. Studies in ASD cohorts have identified EZH2 sequence variants associated with the condition, where reduced EZH2 activity fails to repress autism risk genes in the medial prefrontal cortex, altering social behaviors and synaptic plasticity.^[73] Conditional knockout models in mice demonstrate that Ezh2 loss in neurons leads to increased dendritic spine density and synaptic gene expression, mimicking ASD-like phenotypes such as impaired social interaction.^[74] These findings suggest that PRC2-mediated silencing is essential for maintaining synaptic homeostasis, and its disruption contributes to neurodevelopmental vulnerabilities.^[73] PRC2 also plays a role in age-related and fibrotic disorders through its involvement in cellular senescence. In senescent cells, PRC2 activity diminishes, leading to loss of H3K27me3 and derepression of inflammatory genes, which exacerbates tissue remodeling in conditions like idiopathic pulmonary fibrosis (IPF).^[75] Dysregulated PRC2 in adult lung epithelium promotes fibroblast activation and extracellular matrix deposition, driving progressive fibrosis in IPF lungs, where reduced EZH2 expression correlates with increased senescent markers and inflammatory signaling.^[75]^[76] This senescence-associated PRC2 decline highlights its protective role against chronic inflammation and fibrosis in aging tissues.^[75] Rare mutations in PRC2 components extend to other disorders, including SUZ12 variants discovered in 2014 that disrupt complex assembly and contribute to endometrial stromal sarcoma, a rare uterine disorder with overgrowth-like features in affected tissues. Additionally, germline SUZ12 variants cause Imagawa-Matsumoto syndrome, an overgrowth disorder with intellectual disability and dysmorphic features, resulting from haploinsufficiency that impairs PRC2-mediated gene repression during development.^[77]^[78] These examples illustrate the broad impact of PRC2 perturbations in non-malignant syndromes involving growth dysregulation and epigenetic instability.^[78]

PRC2 in plants

Plant-specific components

In Arabidopsis thaliana, the Polycomb Repressive Complex 2 (PRC2) incorporates core subunits homologous to those in animals, but features plant-specific paralogs that enable functional diversification.^[8] The SU(Z)12 homologs include three genes: VERNALIZATION2 (VRN2), which promotes flowering repression during vernalization and is enriched in the shoot apex; EMBRYONIC FLOWER2 (EMF2), which maintains the vegetative phase; and FERTILIZATION-INDEPENDENT SEED2 (FIS2), which functions in reproductive tissues such as the endosperm.^[8]^[79] These homologs exhibit tissue-specific expression patterns, with VRN2 predominantly active in the shoot apical meristem to modulate photoperiod-dependent flowering.^[79] The EZH2 homologs comprise three paralogs: CURLY LEAF (CLF) and SWINGER (SWN), which show functional redundancy in regulating vegetative growth and flowering; and MEDEA (MEA), which is essential for seed development and displays maternal imprinting in the endosperm, where only the maternal allele is expressed.^[80]^[81] MEA's imprinting ensures parent-of-origin-specific monoallelic expression post-fertilization, contributing to endosperm cellularization.^[81] The EED homolog is a single gene, FERTILIZATION-INDEPENDENT ENDOSPERM (FIE), which is ubiquitously expressed and serves as a common subunit across PRC2 variants, facilitating allosteric regulation similar to its animal counterparts.^[80] For the RbAp homolog, Arabidopsis encodes five MSI1-like genes (MSI1–MSI5), with MSI1 (MULTICOPY SUPPRESSOR OF IRA1) being the primary PRC2 component, integrating with other subunits to support H3K27 methylation during development.^[82] These subunits assemble into three distinct PRC2 subtypes tailored to developmental stages: the FIS complex (FIS2, MEA, FIE, MSI1) for seed and endosperm regulation; the EMF complex (EMF2, CLF or SWN, FIE, MSI1) for embryonic and vegetative maintenance; and the VRN complex (VRN2, CLF or SWN, FIE, MSI1) for vernalization-mediated flowering control.^[80] Compared to animals, plant PRC2 lacks an EZH1 paralog and exhibits greater redundancy among EZH2-like proteins (CLF, SWN, MEA), allowing context-specific complex formation without a low-activity EZH1 equivalent.^[83]

Functions in plant development

In plants, PRC2 plays a pivotal role in regulating flowering time through the VRN-PRC2 complex, which mediates vernalization by repressing the floral repressor FLOWERING LOCUS C (FLC) in response to prolonged cold exposure. During vernalization, cold induces the stable deposition of H3K27me3 at the FLC locus, leading to its epigenetic silencing and promotion of flowering upon warming; this process involves the VRN2 subunit of PRC2 and requires accessory factors like VERNALIZATION INSENSITIVE 3 (VIN3) for nucleation and spreading of the repressive mark.^[84]^[85] Mutations in VRN-PRC2 components, such as vrn2, result in failure to repress FLC, causing late flowering even after cold treatment, highlighting PRC2's essential function in seasonally timed reproductive transitions. During embryogenesis and seed development, the FIS-PRC2 complex represses endosperm proliferation and controls imprinting to ensure proper seed viability post-fertilization. FIS-PRC2, comprising subunits like FERTILIZATION-INDEPENDENT SEED 2 (FIS2) and MEDEA (MEA), acts in the female gametophyte to prevent autonomous endosperm development before pollination; mutants such as mea or fis2 exhibit seed abortion due to overproliferation of unfertilized endosperm, demonstrating PRC2's role in coupling fertilization to seed initiation.^[86]^[87] In fertilized seeds, FIS-PRC2 maintains repression of paternal alleles of target genes, including those involved in nutrient allocation, thereby coordinating embryo and endosperm growth.^[88] PRC2 contributes to stem cell maintenance in vegetative meristems via the EMF-PRC2 complex, which silences floral identity genes to sustain indeterminate growth. EMF-PRC2, including CURLY LEAF (CLF) and SWINGER (SWN) subunits, deposits H3K27me3 on loci like AGAMOUS and APETALA3 in shoot apical meristems, preventing precocious flowering; double mutants clf swn display curled leaves and immediate floral conversion upon germination, underscoring PRC2's necessity for vegetative phase prolongation.^[89] This repression integrates with hormonal signals, such as auxin, to balance proliferation and differentiation in meristematic tissues.^[90] Genome imprinting in plants is exemplified by MEA, a FIS-PRC2 subunit that autoregulates its own expression through parent-of-origin-specific H3K27me3 deposition. In the endosperm, maternal MEA activates FIS-PRC2 to trimethylate H3K27 on the paternal MEA allele, silencing it and reinforcing maternal bias; this feedback loop ensures imprinted expression critical for seed development, as mea mutants disrupt both self-regulation and downstream targets.^[91]^[92] Such mechanisms contribute to dosage-dependent control of seed size and viability by distinguishing parental genomes.^[93] PRC2 also integrates environmental stress signals into developmental decisions, such as derepressing targets under drought to modulate growth. In response to abscisic acid (ABA) signaling during drought, PRC2 attenuates stress-responsive gene expression by maintaining H3K27me3 on promoters of dehydration-inducible loci, balancing survival and reproduction; clf mutants show hypersensitivity to drought due to ectopic derepression of these targets.^[94] This regulatory flexibility allows PRC2 to fine-tune phenotypic plasticity, as seen in interactions with stress factors like BLISTER, which modulates PRC2 activity to repress drought-adaptive genes under non-stress conditions.^[95]

Regulation of PRC2 activity

Post-translational modifications

Post-translational modifications (PTMs) of PRC2 subunits, including phosphorylation, ubiquitination, acetylation, and sumoylation, play crucial roles in regulating complex assembly, catalytic activity, substrate binding, and localization, thereby fine-tuning its epigenetic functions in gene repression. These modifications respond to cellular signals such as growth factors, stress, and cell cycle progression, ensuring PRC2 activity aligns with physiological demands. For instance, phosphorylation events often modulate PRC2's methyltransferase activity toward histone H3 lysine 27 (H3K27), while ubiquitination influences subunit stability. Phosphorylation is a predominant PTM on PRC2 core subunits, particularly EZH2 and SUZ12, and is mediated by various kinases to control enzymatic output and complex integrity. AKT (also known as PKB) phosphorylates EZH2 at serine 21 (S21), which inhibits its methyltransferase activity and reduces H3K27me3 levels by impairing EZH2's association with histone H3 tails.^[96] In contrast, cyclin-dependent kinases (CDK1 and CDK2) phosphorylate EZH2 at threonine 345 (T345), threonine 416 (T416), and threonine 487 (T487) in a cell cycle-dependent manner, promoting EZH2's interaction with non-coding RNAs like HOTAIR and the phosphatase inhibitor NIPP1 to enhance targeting to specific genomic loci during interphase.^[97] These phosphorylation events on EZH2 can also disrupt PRC2 assembly; for example, AMPK phosphorylates EZH2 at T311, while JAK3 targets Y244 and CDK1 targets T487, leading to dissociation of EZH2 from SUZ12 and reduced H3K27 methylation. On SUZ12, polo-like kinase 1 (PLK1) phosphorylates serines 539, 541, and 546 (S539/S541/S546), which weakens EZH2 binding and promotes SUZ12 ubiquitination and degradation, thereby inactivating PRC2 during mitosis. Ubiquitination primarily affects PRC2 subunit stability, often triggered by prior phosphorylation to mark components for proteasomal degradation. For EZH2, phosphorylation at sites like Y641 (by JAK2) and T261 (by CDK5) recruits E3 ligases such as β-TRCP/FBXW11 and FBXW7, leading to polyubiquitination and degradation, which limits PRC2 activity during differentiation or stress responses. Additionally, the E3 ligase Smurf2 ubiquitinates EZH2 at lysine 421 (K421), facilitating its turnover in post-mitotic neurons to derepress developmental genes. The deubiquitinase 3 (USP3) counteracts this by removing ubiquitin from SUZ12, stabilizing the subunit and maintaining PRC2 integrity, while USP21 similarly protects EZH2 from degradation. Acetylation modifies EZH2 to influence its stability and repressive function. The acetyltransferase PCAF (p300/CBP-associated factor) acetylates EZH2 at lysine 348 (K348), which enhances EZH2 protein levels by inhibiting its phosphorylation at T345/T487 and subsequent ubiquitination, thereby promoting stronger H3K27me3 deposition and gene silencing. This modification is reversed by SIRT1 deacetylation, providing a dynamic switch for PRC2 activity. Sumoylation has been identified on PRC2 subunits, though its functional impacts are less characterized. PIASXβ sumoylates SUZ12 at lysine 75 (K75), but this does not alter SUZ12 localization or PRC2 catalytic activity, suggesting context-specific roles that remain unclear. Multiple sumoylation sites on EZH2 have been detected in proteomic studies, potentially linking PRC2 to broader sumo-mediated networks in chromatin regulation. PRC2 PTMs exhibit cell cycle-dependent dynamics, with hypophosphorylated forms predominant in G1 phase to support high methyltransferase activity and gene repression during proliferation. In mitosis, hyperphosphorylation of EZH2 (by CDK1 at T345/T487) and SUZ12 (by PLK1 at S539/S541/S546) inactivates PRC2, preventing ectopic H3K27 methylation on condensed chromosomes, and facilitates subunit turnover for post-mitotic reactivation.^[97] This temporal regulation ensures PRC2's role in maintaining epigenetic memory across divisions.

Interactions with non-coding RNAs and other factors

Long non-coding RNAs (lncRNAs) play a critical role in recruiting PRC2 to specific genomic loci, thereby facilitating targeted H3K27 methylation. The lncRNA Xist, essential for X-chromosome inactivation, directly binds to the EZH2 subunit of PRC2 through its conserved A-repeat region, enabling PRC2 recruitment to the inactive X chromosome and subsequent gene silencing. Similarly, the lncRNA HOTAIR, transcribed from the HOXC locus, interacts with PRC2 to promote its occupancy at the HOXD locus, where it coordinates with PRC1 to establish repressive chromatin domains and regulate Hox gene expression during development.^[98] Circular RNAs (circRNAs) can indirectly enhance PRC2 activity by acting as miRNA sponges, thereby derepressing miRNAs that would otherwise inhibit PRC2 components. For instance, certain circRNAs sequester miRNAs targeting EZH2, leading to increased EZH2 expression and elevated H3K27me3 levels at target sites. This mechanism contributes to PRC2-mediated repression in contexts such as cellular differentiation and disease. PRC2 also engages with chromatin readers to modulate its distribution and function within heterochromatic regions. The heterochromatin protein 1 (HP1) interacts with PRC2 subunits, including EZH2 and SUZ12, to stabilize HP1 binding at chromatin marked by both H3K27me3 and H3K9me3, promoting the cooperative spreading of repressive marks and maintenance of heterochromatin integrity. Conversely, the H3K27 demethylases UTX and JMJD3 antagonize PRC2 by removing H3K27me3 marks, thereby counteracting Polycomb-mediated silencing and facilitating gene activation, particularly at developmental loci such as Hox genes.^[99] Transcription factors further direct PRC2 recruitment to lineage-specific targets. In neuronal gene regulation, the repressor element-1 silencing transcription factor (REST) physically interacts with PRC2, enabling its binding to promoters of neuronal differentiation genes and enforcing repression through H3K27me3 deposition.^[100] Similarly, methyl-CpG-binding protein 2 (MeCP2) co-enriches with PRC2 at neuronal loci by recognizing H3K27me3, amplifying repression of non-neuronal genes during brain development.^[101] In hematopoiesis, GATA factors, such as GATA2, modulate PRC2 composition and targeting, restricting its activity to maintain hematopoietic stem cell identity while repressing alternative lineage programs.^[102] Inhibitory factors prevent aberrant PRC2 activity at non-target sites. JARID2, a PRC2 cofactor, forms complexes with nucleosomes that block PRC2's methyltransferase activity at off-target regions, thereby restricting H3K27me3 spreading and ensuring precise genomic targeting during differentiation. Recent studies show that accessory subunits like JARID2 and PALI1 mimic H3K27me3 to allosterically restrict PRC2 spreading, ensuring targeted repression during development.^[103] This dual role of JARID2—promoting recruitment at targets while inhibiting ectopic methylation—maintains epigenetic fidelity.^[104]

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Polycomb Repressive Complexes, PRC1 and PRC2, are bound at and repress the activity of a large number of key developmental genes in ES cells and at different ...
[82]
MeCP2 regulates gene expression through recognition of H3K27me3
Jun 19, 2020 · In this study, we demonstrate that MeCP2 can be recruited to genomic loci via binding to H3K27me3 and co-enrichment of MeCP2 and H3K27me3 at transcription ...Missing: REST PRC2
[83]
Accessory subunits of PRC2 mimic H3K27me3 to restrict the spread ...
Mar 13, 2025 · We show that H3K27me3 mimicry evolved to compete against the PRC2-H3K27me3 read-write loop in a process that restrains PRC2 and restricts the spread of ...Missing: circular RNAs