EZH2
Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene.
EZH2 participates in histone methylation and, ultimately, transcriptional repression.
It catalyzes the addition of methyl groups to histone H3 at lysine 27 by using the cofactor S-adenosyl-L-methionine.
Methylation activity of EZH2 facilitates heterochromatin formation silencing gene function.
Remodeling of chromosomal heterochromatin by EZH2 is required during cell mitosis.
Gene location Chromosome 7.
EZH2 typically is not expressed in healthy adult cells.
EZH2 is only found in actively dividing cells, like those active during fetal development.
EZH2 is the functional enzymatic component of the Polycomb Repressive Complex 2 (PRC2).
PRC2 is responsible for embryonic development by epigenetic maintenance of genes responsible for regulating development and differentiation.
Mutation or over-expression of EZH2 is associated withmany forms of cancer.
It inhibits genes responsible for suppressing tumor development, and blocking EZH2 activity may slow tumor growth.
It is upregulated in multiple cancers including: breast, prostate, melanoma, and bladder cancer.
Mutations in the EZH2 gene are also associated with Weaver syndrome.
Weaver syndrome is a rare congenital disorder, and EZH2 causes neurodegenerative symptoms in the nervous system disorder, ataxia telangiectasia.
EZH2 is capable of mono-, di-, and tri-methylation and has been associated with a variety of biological functions, including transcriptional regulation in hematopoiesis, development, and cell differentiation.
EZH2 may also be capable of methylating non-histone proteins.
Chemical modifications, as methylation, of histone proteins play roles in epigenetic regulation of gene transcription.
EZH2-mediated catalysis of histone H3 at lysine 27 is associated with long term transcription repression.
EZH2 helps establish and maintains gene repression through cell division.
This transcriptionally repressive state is thought to be due to methylation and subsequent recruitment of PRC1 which facilitates condensation of chromatin and formation of heterochromatin.
Heterochromatin is tightly packed chromatin.
The tightly packed chromatin limits the accessibility of transcription machinery to the underlying DNA and suppresses transcription.
During cell division, heterochromatin formation is required for proper chromosome segregation.
PRC2/EED-EZH2 complex may also be involved in the recruitment of DNA methyltransferases, which increases DNA methylation, another epigenetic layer of transcription repression.
Genes targets of EZH2-mediated transcriptional repression include HOXA9, HOXC8, MYT1, CDKN2A and retinoic acid target genes.
EZH2 may play a role in activation of transcription, independently of PRC2.
In breast cancer cells, EZH2 has been demonstrated to activate NF-κB target genes, which are involved in responses to stimuli.
EZH2 plays an essential role the control of transcriptional repression of genes that regulate cell differentiation.
In embryonic stem cells, EZH2 appears to be important for maintenance of normal cell differentiation.
Histone H3 at lysine 27 (H3K27me3) is important in driving X-inactivation, the silencing of one X-chromosome in females during development.
During X-inactivation EZH2 initiates heterochromatin formation by trimethylating H3K27 and that other histone methyltransferases and histone marks may be involved in maintaining the silenced state.
EZH2 is an essential protein involved in development and differentiation of B-cells and T-cells.
H3K27me3 suppresses genes that promote differentiation, thus maintaining an undifferentiated state of B- and T-cells and playing an important role in regulating hematopoiesis.
The activity of EZH2 is regulated by the post-translational phosphorylation of threonine and serine residues on EZH2.
EZH2 function is highly dependent upon its recruitment by the PRC2 complex.
Part of the silencing function of the EZH2 complex is the methylation of histone H3 on lysine.
EZH2 helps cancerous cells divide and proliferate.
EZH2 is present in larger amounts than in healthy cells in a wide range of cancers including: breast, prostate, bladder, uterine, renal cancers, as well as melanoma and lymphoma.
It acts as a gene suppressor, so when it becomes overexpressed, many tumor suppressor genes that are normally turned on, are turned off.
Inhibition of EZH2 function can decrease malignant tumors in some reported cases because those tumor suppressor genes are not silenced by EZH2.
Overexpression of EZH2 can be used as a diagnostic marker of cancer and some neurodegenerative disorders.
EZH2 activates genes that promote cell proliferation and survival.
EZH2 activates regulatory genes like c-myc and cyclin D1.
Blocking EZH2 activity by binding to the SET domain active site of the enzyme is a therapeutic goal to treat malignancies (tazemetostat).
Mutations in the EZH2 gene have been linked with Weaver syndrome, which is a disorder characterized by advanced bone age, macrocephaly, and hypertelorism.
In the Weaver syndrome the histidine residue in the active site of wild-type EZH2 mutates to tyrosine, and the mutation likely interferes with cofactor binding and causes disruption of the natural function of the protein.
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