The polycomb group (PcG) proteins are a family of proteins responsible for cellular differentiation during development via transcriptional repression. The polycomb group was first described in Drosophila as a locus involved in the silencing of Hox gene expression (Lewis, 1978). Many PcG proteins achieve this control of gene expression via catalyzing H3K27 methylation. These proteins have been the subject of intense study as it is clear that they are vital for maintenance of cell-type identity, differentiation, and disease by creating and maintaining repressive chromatin environments. Most PcG proteins form two major polycomb repressive complexes (PRC): PRC1, and PRC2.
Polycomb Repressive Complexes
When the PRC1 components were first described in Drosophila, four proteins were identified: polycomb (Pc), polyhomeotic (PH), dRING, and posterior sex combs (PSC) (Shao et al., 1999). The human homologs of these proteins are CBXs (Pc homolog), PHC1,2, and 3 (PH homologs), Ring1a and Ring1b (dRING homologs) BMI1 and six minor others (PSC homologs) (Levine et al., 2002).
PRC2 contains three components: enhancer of zeste (EZ), suppressor of zeste 12 (Suz12), extra sex combs (Esc). Polycomblike (Pcl) also often associates with the other PRC2 proteins. The human homologs of these are EZH1/2, SUZ12, embryonic ectoderm development (EED) and RbBP4 respectively. There are additional homologs and variants of these proteins that are best reviewed elsewhere (see Di Croce and Helin 2013).
Polycomb Interactions with Chromatin
Now that all the introductions are out of the way, we can get to the really interesting part: what all these proteins actually do. Put simply, PRC2 first binds to chromatin and its catalytic subunit, EZH2, trimethylates H3K27. H3K27me3 is then recognized by the CBX component of PRC1. The E3 ligases RING1/2 then monoubiquitinates H2A on K119 which leads to chromatin compaction and pausing of RNAPII (Francis et al., 2004).
In Drosophila, polycomb response DNA elements are responsible for the initial recruitment of PRC2 to DNA. This mechanism remains unclear in mammals; however, some clues have emerged. The PRC2 associated protein Jarid2 and the Pcl proteins appear to have some role in targeting the complex to unmethyated CpG islands and other regions. (Hunkapiller et al., 2012; Pasini et al., 2010). Jarid2’s mechanism of targeting in unclear; however, Pcl binds to the transcriptional elongation mark H3K36me (Brien et al., 2012).
Now for some additional tidbits of interesting info about these proteins. EZH2 has a role beyond simply repressing gene expression via H3K27me3. It also serves as a scaffold for DNA methyltransferases thus forming a direct link between histone methylation and DNA methylation at repressed promoters (Vire et al., 2006).
PcG proteins are not only important in development, but are critical to carcinogenesis. BMI1 from PRC1 and EZH2 from PRC2 both have a lot of literature on their oncogenic properties. Both PRC1 and EZH2 are elevated in numerous cancers (Aloia et al., 2013). One way this elevation may be carcinogenic is by reducing self-renewal of stem cells (Dovey et al., 2008; Richter et al., 2009). The PcG group has a massive amount of literature associated with it, and it can’t all be covered in one document. Check out the Additional Reading for some great info on additional, less-known family members and more details about some of the functions of this epigenetic superfamily.
Polycomb Group Protein Additional Reading
Di Croce, L., and Helin, K. (2013). Transcriptional regulation by Polycomb group proteins. Nat. Struct. Mol. Biol. 20, 1147-1155.
This recent review give a great look more of the lesser known attributes of the PcG proteins. This review is for a reader who known about what PcG proteins are, but wants some more detailed information on some key components.
Sauvageau, M., and Sauvageau, G. (2010). Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell. Stem Cell. 7, 299-313.
This review gives great detail on all accept of PcG protein structure and function. The reviews point of view is centered on the role of PcG proteins in regulating stem cell activity, but it also addresses other important roles such as homeostasis and cancer.
- Aloia, L., Di Stefano, B., and Di Croce, L. (2013). Polycomb complexes in stem cells and embryonic development. Development 140, 2525-2534.
- Brien, G.L., Gambero, G., O’Connell, D.J., Jerman, E., Turner, S.A., Egan, C.M., Dunne, E.J., Jurgens, M.C., Wynne, K., Piao, L., et al. (2012). Polycomb PHF19 binds H3K36me3 and recruits PRC2 and demethylase NO66 to embryonic stem cell genes during differentiation. Nat. Struct. Mol. Biol. 19, 1273-1281.
- Dovey, J.S., Zacharek, S.J., Kim, C.F., and Lees, J.A. (2008). Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion. Proc. Natl. Acad. Sci. U. S. A. 105, 11857-11862.
- Francis, N.J., Kingston, R.E., and Woodcock, C.L. (2004). Chromatin compaction by a polycomb group protein complex. Science 306, 1574-1577.
- Hunkapiller, J., Shen, Y., Diaz, A., Cagney, G., McCleary, D., Ramalho-Santos, M., Krogan, N., Ren, B., Song, J.S., and Reiter, J.F. (2012). Polycomb-like 3 promotes polycomb repressive complex 2 binding to CpG islands and embryonic stem cell self-renewal. PLoS Genet. 8, e1002576.
- Levine, S.S., Weiss, A., Erdjument-Bromage, H., Shao, Z., Tempst, P., and Kingston, R.E. (2002). The core of the polycomb repressive complex is compositionally and functionally conserved in flies and humans. Mol. Cell. Biol. 22, 6070-6078.
- Lewis, E.B. (1978). A gene complex controlling segmentation in Drosophila. Nature 276, 565-570.
- Pasini, D., Cloos, P.A., Walfridsson, J., Olsson, L., Bukowski, J.P., Johansen, J.V., Bak, M., Tommerup, N., Rappsilber, J., and Helin, K. (2010). JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. Nature 464, 306-310.
- Richter, G.H., Plehm, S., Fasan, A., Rossler, S., Unland, R., Bennani-Baiti, I.M., Hotfilder, M., Lowel, D., von Luettichau, I., Mossbrugger, I., et al. (2009). EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation. Proc. Natl. Acad. Sci. U. S. A. 106, 5324-5329.
- Shao, Z., Raible, F., Mollaaghababa, R., Guyon, J.R., Wu, C.T., Bender, W., and Kingston, R.E. (1999). Stabilization of chromatin structure by PRC1, a Polycomb complex. Cell 98, 37-46.
- Vire, E., Brenner, C., Deplus, R., Blanchon, L., Fraga, M., Didelot, C., Morey, L., Van Eynde, A., Bernard, D., Vanderwinden, J.M., et al. (2006). The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439, 871-874.