UniProt functional annotation for Q61188



	UniProt functional annotation for Q61188

UniProt code: Q61188.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

Function: Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH2 complex, which methylates (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 HOXA7, HOXB6 and HOXC8. 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- ARNTL/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. {ECO:0000250|UniProtKB:Q15910, ECO:0000269|PubMed:12689588, ECO:0000269|PubMed:15516932, ECO:0000269|PubMed:15520282, ECO:0000269|PubMed:16717091, ECO:0000269|PubMed:18086877, ECO:0000269|PubMed:19026780}.

Catalytic activity: Reaction=L-lysyl(27)-[histone H3] + 3 S-adenosyl-L-methionine = 3 H(+) + N(6),N(6),N(6)-trimethyl-L-lysyl(27)-[histone H3] + 3 S-adenosyl-L- homocysteine; Xref=Rhea:RHEA:60292, Rhea:RHEA-COMP:15535, Rhea:RHEA- COMP:15548, ChEBI:CHEBI:15378, ChEBI:CHEBI:29969, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:61961; EC=2.1.1.356; Evidence={ECO:0000250|UniProtKB:Q15910};

Subunit: Component of the PRC2/EED-EZH2 complex, which includes EED, EZH2, SUZ12, RBBP4 and RBBP7 and possibly AEBP2 (By similarity). The minimum components required for methyltransferase activity of the PRC2/EED-EZH2 complex are EED, EZH2 and SUZ12 (By similarity). The PRC2 complex may also interact with DNMT1, DNMT3A, DNMT3B and PHF1 via the EZH2 subunit and with SIRT1 via the SUZ12 subunit (By similarity). Interacts with HDAC1 and HDAC2 (By similarity). Binds ATRX via the SET domain (By similarity). Interacts with PRAME (By similarity). Interacts with CDYL (By similarity). Interacts with EED. Interacts with ARNTL/BMAL1. Interacts with CLOCK and CRY1. Interacts with DNMT3L; the interaction is direct (PubMed:24074865). Interacts with EZHIP; the interaction blocks EZH2 methyltransferase activity (PubMed:31451685). Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression (By similarity). {ECO:0000250|UniProtKB:Q15910, ECO:0000269|PubMed:16717091, ECO:0000269|PubMed:17259173, ECO:0000269|PubMed:17937919, ECO:0000269|PubMed:19026780, ECO:0000269|PubMed:20144788, ECO:0000269|PubMed:23970558, ECO:0000269|PubMed:24074865, ECO:0000269|PubMed:31451685, ECO:0000269|PubMed:9742080}.

Subcellular location: Nucleus {ECO:0000269|PubMed:12123576}. Chromosome. Note=Localizes to the inactive X chromosome in trophoblast stem cells. {ECO:0000269|PubMed:12123576}.

Tissue specificity: Present in actively dividing cells (PubMed:19026781). Widely expressed in early embryos (PubMed:19026781). In later embryogenesis, expression restricted to central and peripheral nervous system, liver and thymus (PubMed:19026781). In adult, highest expression in spleen, testis and placenta (PubMed:19026781, PubMed:31451685). Lower levels in intestine, muscle and ovary and very low levels in brain and liver (PubMed:19026781, PubMed:31451685). No expression in heart, thyroid gland, lung and kidney (PubMed:19026781). {ECO:0000269|PubMed:19026781, ECO:0000269|PubMed:31451685}.

Developmental stage: Expressed in both adult and embryo with highest levels in early embryogenesis. Expressed in the fertilized oocyte. Expression decreases during differentiation of ES cells and during senescence of MEFs. Expression increases in prostate during prostate tumor development. {ECO:0000269|PubMed:12689588, ECO:0000269|PubMed:15684044, ECO:0000269|PubMed:17344414}.

Induction: Repressed by the microRNA (miRNA) miR-26a. {ECO:0000269|PubMed:18281287}.

Ptm: Phosphorylated by AKT1 (By similarity). Phosphorylation by AKT1 reduces methyltransferase activity. Phosphorylation at Thr-345 by CDK1 and CDK2 promotes maintenance of H3K27me3 levels at EZH2-target loci, thus leading to epigenetic gene silencing (By similarity). {ECO:0000250|UniProtKB:Q15910}.

Ptm: Sumoylated. {ECO:0000250|UniProtKB:Q15910}.

Ptm: Glycosylated: O-GlcNAcylation at Ser-75 by OGT increases stability of EZH2 and facilitates the formation of H3K27me3 by the PRC2/EED-EZH2 complex. {ECO:0000250|UniProtKB:Q15910}.

Disruption phenotype: Death early in development. Embryos cease development following implantation or initiate but fail to complete gastrulation. {ECO:0000269|PubMed:11390661}.

Similarity: Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. EZ subfamily. {ECO:0000255|PROSITE-ProRule:PRU00190}.

Sequence caution: Sequence=AAD54020.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



Function:		Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH2 complex, which methylates (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 HOXA7, HOXB6 and HOXC8. 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- ARNTL/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. {ECO:0000250\|UniProtKB:Q15910, ECO:0000269\|PubMed:12689588, ECO:0000269\|PubMed:15516932, ECO:0000269\|PubMed:15520282, ECO:0000269\|PubMed:16717091, ECO:0000269\|PubMed:18086877, ECO:0000269\|PubMed:19026780}.


Catalytic activity:		Reaction=L-lysyl(27)-[histone H3] + 3 S-adenosyl-L-methionine = 3 H(+) + N(6),N(6),N(6)-trimethyl-L-lysyl(27)-[histone H3] + 3 S-adenosyl-L- homocysteine; Xref=Rhea:RHEA:60292, Rhea:RHEA-COMP:15535, Rhea:RHEA- COMP:15548, ChEBI:CHEBI:15378, ChEBI:CHEBI:29969, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:61961; EC=2.1.1.356; Evidence={ECO:0000250\|UniProtKB:Q15910};
Subunit:		Component of the PRC2/EED-EZH2 complex, which includes EED, EZH2, SUZ12, RBBP4 and RBBP7 and possibly AEBP2 (By similarity). The minimum components required for methyltransferase activity of the PRC2/EED-EZH2 complex are EED, EZH2 and SUZ12 (By similarity). The PRC2 complex may also interact with DNMT1, DNMT3A, DNMT3B and PHF1 via the EZH2 subunit and with SIRT1 via the SUZ12 subunit (By similarity). Interacts with HDAC1 and HDAC2 (By similarity). Binds ATRX via the SET domain (By similarity). Interacts with PRAME (By similarity). Interacts with CDYL (By similarity). Interacts with EED. Interacts with ARNTL/BMAL1. Interacts with CLOCK and CRY1. Interacts with DNMT3L; the interaction is direct (PubMed:24074865). Interacts with EZHIP; the interaction blocks EZH2 methyltransferase activity (PubMed:31451685). Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression (By similarity). {ECO:0000250\|UniProtKB:Q15910, ECO:0000269\|PubMed:16717091, ECO:0000269\|PubMed:17259173, ECO:0000269\|PubMed:17937919, ECO:0000269\|PubMed:19026780, ECO:0000269\|PubMed:20144788, ECO:0000269\|PubMed:23970558, ECO:0000269\|PubMed:24074865, ECO:0000269\|PubMed:31451685, ECO:0000269\|PubMed:9742080}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:12123576}. Chromosome. Note=Localizes to the inactive X chromosome in trophoblast stem cells. {ECO:0000269\|PubMed:12123576}.
Tissue specificity:		Present in actively dividing cells (PubMed:19026781). Widely expressed in early embryos (PubMed:19026781). In later embryogenesis, expression restricted to central and peripheral nervous system, liver and thymus (PubMed:19026781). In adult, highest expression in spleen, testis and placenta (PubMed:19026781, PubMed:31451685). Lower levels in intestine, muscle and ovary and very low levels in brain and liver (PubMed:19026781, PubMed:31451685). No expression in heart, thyroid gland, lung and kidney (PubMed:19026781). {ECO:0000269\|PubMed:19026781, ECO:0000269\|PubMed:31451685}.
Developmental stage:		Expressed in both adult and embryo with highest levels in early embryogenesis. Expressed in the fertilized oocyte. Expression decreases during differentiation of ES cells and during senescence of MEFs. Expression increases in prostate during prostate tumor development. {ECO:0000269\|PubMed:12689588, ECO:0000269\|PubMed:15684044, ECO:0000269\|PubMed:17344414}.
Induction:		Repressed by the microRNA (miRNA) miR-26a. {ECO:0000269\|PubMed:18281287}.
Ptm:		Phosphorylated by AKT1 (By similarity). Phosphorylation by AKT1 reduces methyltransferase activity. Phosphorylation at Thr-345 by CDK1 and CDK2 promotes maintenance of H3K27me3 levels at EZH2-target loci, thus leading to epigenetic gene silencing (By similarity). {ECO:0000250\|UniProtKB:Q15910}.
Ptm:		Sumoylated. {ECO:0000250\|UniProtKB:Q15910}.
Ptm:		Glycosylated: O-GlcNAcylation at Ser-75 by OGT increases stability of EZH2 and facilitates the formation of H3K27me3 by the PRC2/EED-EZH2 complex. {ECO:0000250\|UniProtKB:Q15910}.
Disruption phenotype:		Death early in development. Embryos cease development following implantation or initiate but fail to complete gastrulation. {ECO:0000269\|PubMed:11390661}.
Similarity:		Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. EZ subfamily. {ECO:0000255\|PROSITE-ProRule:PRU00190}.
Sequence caution:		Sequence=AAD54020.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};