polycomb group proteins
Polycomb group proteins are important for the somatic maintenance of imprinting and for maintaining the silenced state of homeotic genes.
The chromatin-associated Polycomb Group (PcG) proteins were first identified in genetic screens for homeotic transformations in Drosophila melanogaster.
In addition to body patterning in metazoans, members of the PcG are now known to regulate epigenetic cellular memory, pluripotency and stem cell self-renewal.
Genes belonging to the Polycomb-group (PcG) are epigenetic gene silencers with a vital role in the maintenance of cell identity. They contribute to regulation of various processes in both embryos and adults, including the cell cycle and lymphopoiesis.
Human PcG genes are linked to various hematological and epithelial cancers, identifying novel mechanisms of malignant transformation and paving the way to development of new cancer treatments and identification of novel diagnostic markers.
Biochemical and genetic studies in Drosophila and mammalian cells indicate that PcG proteins function in at least two distinct protein complexes: the ESC-E(Z) or EED-EZH2 complex, and the PRC1 complex.
Functions
silencing function
- at least part of the silencing function of the ESC-E(Z) complex is mediated by its intrinsic activity for methylating histone H3 on lysine 27
involved in Hox gene silencing, X-inactivation, germline development, stem cell pluripotency and cancer metastasis
histone methyltransferase activity
Polycomb imprints
Polycomb-group (PcG) proteins form transcriptional repressor modules that functionally can be divided into at least two distinct complexes: the initiation complex, Polycomb repression complex 2 (PRC2), the core of which in humans consists of EZH2, EED, and SUZ12; and the maintenance complex, PRC1, with the core proteins RNF2, HPC, EDR, and BMI1.
Both PRC1 and PRC2 complex members have been linked to cell cycle control and cancer. Together with the Trithorax group (TrxG) of proteins, which form positively acting transcriptional regulators (see following), the PcG complexes are thought to constitute a cellular memory system responsible for maintaining the epigenetic status of target genes throughout the lifetime of the organism.
Members of both PcG and TrxG protein complexes harbor SET domains. The SET domain present in EZH2 is responsible for methylation of Lys 9 and, more prominently, Lys 27 of histone H3 and Lys 26 on histone H1.
Interestingly, emerging data suggest that the PRC2 complex composition may influence the type of methylation imprint imposed by EZH2, thereby adding yet another level of regulation.
EZH2 is overexpressed in many cancers and the expression level of EZH2 correlates with a poorer prognosis in both prostate and breast cancer.
Although PRC2 complex members are directly controlled by the RB tumor-suppressor pathway, their expression levels do not appear to fluctuate in a cell cycle-dependent manner.
RNAi-mediated knockdown of EZH2 or EED in human primary or transformed cells results in a block of proliferation, and the observed overexpression of EZH2 in cancers is likely causally related to tumorigenesis and not a mere consequence of deregulated RB-E2F functioning, as the EZH2 locus is amplified in several cancers. This, however, remains to be confirmed in mouse models.
The oncogenic mechanism underlying EZH2 overexpression is unknown. It has been speculated that EZH2 overexpression may exert dominant negative effects on PRC2 complex functions; however, experimental overexpression of EZH2 results in target gene suppression only, and hence does not sustain a notion of dominant negative effects.
The PRC2 complex is also required for X-chromosome inactivation and for correct imprinting of autosomal loci. These functions point to long-range mechanisms of transcriptional repression and suggest that PRC2 activity may have global consequences to the cell, perhaps via more generally skewing the balance between specific histone methylation imprints.
Cancer
Polycomb group (PcG) proteins are epigenetic gene silencers that are implicated in neoplastic development. Their oncogenic function might be associated with their well-established role in the maintenance of embryonic and adult stem cells.
References
Whitcomb SJ, Basu A, Allis CD, Bernstein E. Polycomb Group proteins: an evolutionary perspective. Trends Genet. 2007 Oct;23(10):494-502. PMID: #17825942#
Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J, Eden E, Yakhini Z, Ben-Shushan E, Reubinoff BE, Bergman Y, Simon I, Cedar H. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet. 2007 Feb;39(2):232-6. PMID: #17200670#
Sparmann A, van Lohuizen M. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006 Nov;6(11):846-56. PMID: #17060944#
Raaphorst FM. Deregulated expression of Polycomb-group oncogenes in human malignant lymphomas and epithelial tumors. Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R93-R100. PMID: #15809278#
Cao R, Zhang Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr Opin Genet Dev. 2004 Apr;14(2):155-64. PMID: #15196462#
Gerasimova, T. I., and V. G. Corces. 1998. Polycomb and Trithorax group proteins mediate the function of a chromatin insulator. Cell 92:511-521.
(|IMG/pdf/poly_group_proteins_and_cancer.pdf)