Histone-lysine N-methyltransferase EZH2

Function

Catalytic subunit of the PRC2/EED-EZH2 complex, a Polycomb group (PcG) complex that methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Displays a preference for substrates with less methylation, loses activity when progressively more methyl groups are incorporated into H3K27, H3K27me0 > H3K27me1 > H3K27me2. Compared to EZH1-containing complexes, it is more abundant in embryonic stem cells and plays a major role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1, CDKN2A and retinoic acid target genes. EZH2 can also methylate non-histone proteins such as the transcription factor GATA4 and the nuclear receptor RORA. Regulates the circadian clock via histone methylation at the promoter of the circadian genes. Essential for the CRY1/2-mediated repression of the transcriptional activation of PER1/2 by the CLOCK-BMAL1 heterodimer; involved in the di and trimethylation of 'Lys-27' of histone H3 on PER1/2 promoters which is necessary for the CRY1/2 proteins to inhibit transcription (By similarity).

Classification

Family (Pfam)

PF21358 Ezh2_MCSS, PF11616 EZH2_WD-Binding, PF18118 PRC2_HTH_1, PF18264 preSET_CXC, PF00856 SET

InterPro

CXC_dom, EZH1/2-like, EZH1/2_MCSS, EZH1/EZH2, EZH2_SET, PRC2_HTH_1, Pre-SET_CXC, SANT/Myb, SET_dom, SET_dom_sf, Tesmin/TSO1-like_CXC

Functional cluster

Zinc-Finger Nucleic-Acid-Binding & Methyltransferases

Experimental structures · PDB · 38

• 4MI0 X-ray 2.00A
• 4MI5 X-ray 2.00A
• 5GSA X-ray 2.49A
• 5H14 X-ray 1.90A
• 5H15 X-ray 2.27A
• 5H17 X-ray 2.30A
• 5H19 X-ray 1.90A
• 5H24 X-ray 2.50A
• 5H25 X-ray 2.88A
• 5HYN X-ray 2.95A
• 5IJ7 X-ray 2.62A
• 5IJ8 X-ray 2.99A
• … and 26 more

A predicted model is available from AlphaFold.

Gene Ontology · 57

• GO:0000785 chromatin
• GO:0005677 chromatin silencing complex
• GO:0005694 chromosome
• GO:0000781 chromosome, telomeric region
• GO:0035098 ESC/E(Z) complex
• GO:0000792 heterochromatin
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0005721 pericentric heterochromatin
• GO:0045120 pronucleus
• GO:0045202 synapse
• GO:0003682 chromatin binding
• GO:0031490 chromatin DNA binding
• GO:0042393 histone binding
• GO:0140938 histone H3 methyltransferase activity
• GO:0046976 histone H3K27 methyltransferase activity
• GO:0140951 histone H3K27 trimethyltransferase activity
• GO:0042054 histone methyltransferase activity
• GO:0106222 lncRNA binding
• GO:0031491 nucleosome binding
• GO:0070878 primary miRNA binding
• GO:1990841 promoter-specific chromatin binding
• GO:0016279 protein-lysine N-methyltransferase activity
• GO:0043021 ribonucleoprotein complex binding
• GO:0003723 RNA binding
• GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
• GO:0000979 RNA polymerase II core promoter sequence-specific DNA binding
• GO:0003714 transcription corepressor activity
• GO:0001222 transcription corepressor binding
• GO:0030183 B cell differentiation
• GO:0006325 chromatin organization
• GO:0006351 DNA-templated transcription
• GO:0140718 facultative heterochromatin formation
• GO:0031507 heterochromatin formation
• GO:0021766 hippocampus development
• GO:0032259 methylation
• GO:1900016 negative regulation of cytokine production involved in inflammatory response
• GO:0045892 negative regulation of DNA-templated transcription
• GO:0045814 negative regulation of gene expression, epigenetic
• GO:0048387 negative regulation of retinoic acid receptor signaling pathway
• GO:0000122 negative regulation of transcription by RNA polymerase II
• GO:1902808 positive regulation of cell cycle G1/S phase transition
• GO:0030335 positive regulation of cell migration
• GO:0008284 positive regulation of cell population proliferation
• GO:1900006 positive regulation of dendrite development
• GO:0010718 positive regulation of epithelial to mesenchymal transition
• GO:0043547 positive regulation of GTPase activity
• GO:0043406 positive regulation of MAP kinase activity
• GO:0071902 positive regulation of protein serine/threonine kinase activity
• GO:0042752 regulation of circadian rhythm
• GO:0006355 regulation of DNA-templated transcription
• GO:0090183 regulation of kidney development
• GO:0031048 regulatory ncRNA-mediated heterochromatin formation
• GO:0032355 response to estradiol
• GO:0048511 rhythmic process
• GO:0031509 subtelomeric heterochromatin formation
• GO:0051932 synaptic transmission, GABAergic

Disease associations

• Weaver syndrome MONDO:0010193

Drugs targeting this protein · 2

• GSK2816126 inhibitor
• TAZEMETOSTAT HYDROBROMIDE inhibitor

Related proteins · sequence + function similarity

• Histone-lysine N-methyltransferase EZH2 1.00
• Histone-lysine N-methyltransferase EZH2 0.99
• Histone-lysine N-methyltransferase EZH2 0.98
• Histone-lysine N-methyltransferase EZH2 0.98
• Histone-lysine N-methyltransferase EZH2 0.97
• Histone-lysine N-methyltransferase E(z) 0.93
• Histone-lysine N-methyltransferase EZH1 0.93
• Histone-lysine N-methyltransferase EZH1 0.93
• Histone-lysine N-methyltransferase EZH1 0.93
• Histone-lysine N-methyltransferase EZH1 0.92
• Histone-lysine N-methyltransferase mes-2 0.75
• Histone-lysine N-methyltransferase MEDEA 0.74

Co-cited proteins · studied together in the literature

• Polycomb protein EED 20 shared papers
• Polycomb protein SUZ12 21 shared papers
• EZH inhibitory protein 3 shared papers
• EZH inhibitory protein 2 shared papers
• Histone-lysine N-methyltransferase EZH1 2 shared papers
• Polycomb protein eed-B 1 shared papers
• Histone-lysine N-methyltransferase EZH2 6 shared papers
• Polycomb protein EED 3 shared papers
• Zinc finger protein AEBP2 2 shared papers
• MYND-type zinc finger-containing chromatin reader ZMYND8 2 shared papers
• Chromatin remodeler ATRX 1 shared papers
• Melanoma antigen preferentially expressed in tumors 1 shared papers

Literature · 67 cited papers

• ZMYND8 suppresses MAPT213 LncRNA transcription to promote neuronal differentiation. Cell Death Dis. · 2022
• Suppression of poised oncogenes by ZMYND8 promotes chemo-sensitization. Cell Death Dis. · 2020
• The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically. Oncogene · 2020
• EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells. Nat. Commun. · 2019
• PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism. Nat. Commun. · 2019
• EZHIP / CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma. Neuro-oncol. · 2019
• Armadillo repeat containing 12 promotes neuroblastoma progression through interaction with retinoblastoma binding protein 4. Nat. Commun. · 2018
• Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome. Hum. Mutat. · 2017
• Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation. Nat. Struct. Mol. Biol. · 2017
• Weaver Syndrome-Associated EZH2 Protein Variants Show Impaired Histone Methyltransferase Function In Vitro. Hum. Mutat. · 2016
• Linker histone H1.2 establishes chromatin compaction and gene silencing through recognition of H3K27me3. Sci. Rep. · 2015
• O-GlcNAcylation regulates EZH2 protein stability and function. Proc. Natl. Acad. Sci. U.S.A. · 2014
• … and 55 more in the literature graph