Ezh2 is the is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) and a member of the SET domain family of lysine methyltransferases which function to add methyl groups to lysine side chains of substrate proteins.
Ezh2 is highly conserved through evolution in plants and animals
Ezh2's primary function is as a histone methyltransferase, to methylate Lys-27 on histone 3 (H3K27me) by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) and by catalyzing the trimethylation of H3K27 to form H3K27me3
methylation of histone proteins is a key component of epigenetic regulation of gene transcription.
specific genes that have been identified as targets of EZH2-mediated transcriptional repression include HOXA9, HOXC8, MYT1, CDKN2A and retinoic acid target genes
Ezh2 is also capable of methylating non-histone proteins
Ezh2 typically is not expressed in healthy adults
it is only found in actively dividing cells, like those active during fetal development
some bacterial infections may increase EZH2 levels and thus modify epigenetic regulation 1)
it is over-expressed in some cancers some of which have mutant forms of Ezh2
Ezh2 has key roles in:
development and cell differentiation
appears to be important for maintenance of normal cell differentiation in plants, insects, fish, and mammals
important in driving X-inactivation, the silencing of one X-chromosome in females during development
maybe involved in initiating heterochromatin formation which is required for proper chromosome segregation during cell division
the immune system
EZH2 has been identified as an essential protein involved in development and differentiation of B-cells and T-cells.
Ezh2 appears to be critical to the immune system’s ability to drive inflammation in response to allergens
possible role in some cancers
EZH2 helps cancer cells divide and proliferate
when EZH2 is over-expressed it may turn off tumour suppressor genes
EZH2 is found in higher than normal amounts in various cancers such as breast, prostate, bladder, uterine, and renal cancers, as well as melanoma and lymphoma.
H3K27me3 is involved in suppressing genes that promote differentiation, thus maintaining an undifferentiated state of B- and T-cells and playing an important role in regulating hematopoiesis
Ezh2 gene mutations
Weaver syndrome
a rare disorder characterized by advanced bone age, macrocephaly, and hypertelorism.
seems to switch off the inflammatory component in asthmatic patients 4)
however, EZH2 appears to also be a central regulator of iNKT pathogenicity and suppresses the ability of iNKT cells to induce asthma-like pathology. 5)
inhibitors of the hydrolysis of S-adenosyl-L-homocysteine (SAH)
these are non-specific and inhibit DNA methyltransferases in general (as well as EZH2)
S-adenosylmethionine (SAM) competitive inhibitors
Sinefungin is non-selective
tazemetostat (EPZ-6438)
EPZ005687 is 50x more selective for EZH2 compared to EZH1.
GSK126 is 150x more selective for EZH2 compared to EZH1.