Polycomb-group proteins explained

Polycomb-group proteins (PcG proteins) are a family of protein complexes first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place. Polycomb-group proteins are well known for silencing Hox genes through modulation of chromatin structure during embryonic development in fruit flies (Drosophila melanogaster). They derive their name from the fact that the first sign of a decrease in PcG function is often a homeotic transformation of posterior legs towards anterior legs, which have a characteristic comb-like set of bristles.^[1]

In insects

In Drosophila, the Trithorax-group (trxG) and Polycomb-group (PcG) proteins act antagonistically and interact with chromosomal elements, termed Cellular Memory Modules (CMMs). Trithorax-group (trxG) proteins maintain the active state of gene expression while the Polycomb-group (PcG) proteins counteract this activation with a repressive function that is stable over many cell generations and can only be overcome by germline differentiation processes. Polycomb Gene complexes or PcG silencing consist of at least three kinds of multiprotein complex Polycomb Repressive Complex 1 (PRC1), PRC2 and PhoRC. These complexes work together to carry out their repressive effect. PcGs proteins are evolutionarily conserved and exist in at least two separate protein complexes; the PcG repressive complex 1 (PRC1) and the PcG repressive complex 2–4 (PRC2/3/4). PRC2 catalyzes trimethylation of lysine 27 on histone H3 (H3K27me2/3), while PRC1 mono- ubiquitinates histone H2A on lysine 119 (H2AK119Ub1).

In mammals

In mammals Polycomb Group gene expression is important in many aspects of development like homeotic gene regulation and X chromosome inactivation, being recruited to the inactive X by Xist RNA, the master regulator of XCI^[2] or embryonic stem cell self-renewal.^[3] The Bmi1 polycomb ring finger protein promotes neural stem cell self-renewal.^{[4] [5]} Murine null mutants in PRC2 genes are embryonic lethals while most PRC1 mutants are live born homeotic mutants that die perinatally. In contrast overexpression of PcG proteins correlates with the severity and invasiveness of several cancer types.^[6] The mammalian PRC1 core complexes are very similar to Drosophila. Polycomb Bmi1 is known to regulate ink4 locus (p16^Ink4a, p19^Arf).^[7]

Regulation of Polycomb-group proteins at bivalent chromatin sites is performed by SWI/SNF complexes, which oppose the accumulation of Polycomb complexes through ATP-dependent eviction.^[8]

In plants

In Physcomitrella patens the PcG protein FIE is specifically expressed in stem cells such as the unfertilized egg cell. Soon after fertilisation the FIE gene is inactivated in the young embryo.^[9] The Polycomb gene FIE is expressed in unfertilised egg cells of the moss Physcomitrella patens and expression ceases after fertilisation in the developing diploid sporophyte.

It has been shown that unlike in mammals the PcG are necessary to keep the cells in a differentiated state. Consequently, loss of PcG causes de-differentiation and promotes embryonic development.^[10]

Polycomb-group proteins also intervene in the control of flowering by silencing the Flowering Locus C gene.^[11] This gene is a central part of the pathway that inhibits flowering in plants and its silencing during winter is suspected to be one of the main factors intervening in plant vernalization.^[12]

See also

• PRC1
• PRC2
• PHC1
• PHC2
• Heterochromatin protein 1 (Cbx)
• BMI1
• PCGF1, KDM2B
• PCGF2 (Polycomb group RING finger protein 2) ortolog Bmi1
• RYBP
• RING1
• SUV39H1 (histone-lysine N-methyltransferase)
• L3mbtl2
• EZH2 (Enhancer of Zeste Homolog 2)
• EED
• SUZ12 (Suppressor of Zeste 12)
• Jarid2 (jumonji, AT rich interactive domain 2)
• RE1-silencing transcription factor (REST)
• RNF2
• CBFβ
• YY1
• Bivalent chromatin

Further reading

• Schuettengruber B, Bourbon HM, Di Croce L, Cavalli G . Genome Regulation by Polycomb and Trithorax: 70 Years and Counting . Cell . 171 . 1 . 34–57 . September 2017 . 28938122 . 10.1016/j.cell.2017.08.002 . 43165761 . free .
• Di Croce L, Helin K . Transcriptional regulation by Polycomb group proteins . Nature Structural & Molecular Biology . 20 . 10 . 1147–55 . 2013 . 24096405 . 10.1038/nsmb.2669 . 2681793 .
• Simon JA, Kingston RE . Occupying chromatin: Polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put . Molecular Cell . 49 . 5 . 808–24 . 2013 . 23473600 . 3628831 . 10.1016/j.molcel.2013.02.013 .
• Golbabapour S, Majid NA, Hassandarvish P, Hajrezaie M, Abdulla MA, Hadi AH . Gene silencing and Polycomb group proteins: an overview of their structure, mechanisms and phylogenetics . OMICS: A Journal of Integrative Biology . 17 . 6 . 283–96 . 2013 . 23692361 . 3662373 . 10.1089/omi.2012.0105 .
• Schwartz YB, Pirrotta V . Polycomb silencing mechanisms and the management of genomic programmes . Nature Reviews. Genetics . 8 . 1 . 9–22 . January 2007 . 17173055 . 10.1038/nrg1981 . 28227227 .
• Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G . Genome regulation by polycomb and trithorax proteins . Cell . 128 . 4 . 735–45 . February 2007 . 17320510 . 10.1016/j.cell.2007.02.009 . 6492075 . free .
• Pirrotta V, Li HB . A view of nuclear Polycomb bodies . Current Opinion in Genetics & Development . 22 . 2 . 101–9 . 2012 . 22178420 . 3329586 . 10.1016/j.gde.2011.11.004 .

External links

• Web site: polycomb group proteins . Humpath.com .
• The Polycomb and Trithorax page of the Cavalli lab This page contains useful information on Polycomb and trithorax proteins, in the form of an introduction, links to published reviews, list of Polycomb and trithorax proteins, illustrative power point slides and a link to a genome browser showing the genome-wide distribution of these proteins in Drosophila melanogaster.
• Drosophila Genes in Development: Polycomb-group in the Homeobox Genes DataBase
• Chromatin organization and the Polycomb and Trithorax groups in The Interactive Fly

Notes and References

1. Book: https://books.google.com/books?id=r67Lrf9r9XEC&pg=PA29 . Portoso M, Cavalli G . Morris KV . 2008 . The Role of RNAi and Noncoding RNAs in Polycomb Mediated Control of Gene Expression and Genomic Programming . RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity . Caister Academic Press . 978-1-904455-25-7 . 29–44 .
2. Ku M, Koche RP, Rheinbay E, Mendenhall EM, Endoh M, Mikkelsen TS, Presser A, Nusbaum C, Xie X, Chi AS, Adli M, Kasif S, Ptaszek LM, Cowan CA, Lander ES, Koseki H, Bernstein BE . Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains . PLOS Genetics . 4 . 10 . e1000242 . October 2008 . 18974828 . 2567431 . 10.1371/journal.pgen.1000242 . free .
3. Heurtier, V., Owens, N., Gonzalez, I. et al. The molecular logic of Nanog-induced self-renewal in mouse embryonic stem cells. Nat Commun 10, 1109 (2019). https://doi.org/10.1038/s41467-019-09041-z
4. Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R . Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways . Genes & Development . 19 . 12 . 1432–7 . June 2005 . 15964994 . 1151659 . 10.1101/gad.1299505 .
5. Park IK, Morrison SJ, Clarke MF . Bmi1, stem cells, and senescence regulation . The Journal of Clinical Investigation . 113 . 2 . 175–9 . January 2004 . 14722607 . 311443 . 10.1172/JCI20800 .
6. Sauvageau M, Sauvageau G . Polycomb group genes: keeping stem cell activity in balance . PLOS Biology . 6 . 4 . e113 . April 2008 . 18447587 . 2689701 . 10.1371/journal.pbio.0060113 . free .
7. Popov N, Gil J . Epigenetic regulation of the INK4b-ARF-INK4a locus: in sickness and in health . Epigenetics . 5 . 8 . 685–90 . 2010 . 20716961 . 3052884 . 10.4161/epi.5.8.12996 . .
8. Stanton BZ, Hodges C, Calarco JP, Braun SM, Ku WL, Kadoch C, Zhao K, Crabtree GR . Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin . Nature Genetics . 49 . 2 . 282–288 . February 2017 . 5373480 . 10.1038/ng.3735 . 27941795 .
9. Mosquna A, Katz A, Decker EL, Rensing SA, Reski R, Ohad N . Regulation of stem cell maintenance by the Polycomb protein FIE has been conserved during land plant evolution . Development . 136 . 14 . 2433–44 . July 2009 . 19542356 . 10.1242/dev.035048 . free .
10. Aichinger E, Villar CB, Farrona S, Reyes JC, Hennig L, Köhler C . CHD3 proteins and polycomb group proteins antagonistically determine cell identity in Arabidopsis . PLOS Genetics . 5 . 8 . e1000605 . August 2009 . 19680533 . 2718830 . 10.1371/journal.pgen.1000605 . free .
11. Jiang D, Wang Y, Wang Y, He Y . Repression of FLOWERING LOCUS C and FLOWERING LOCUS T by the Arabidopsis Polycomb repressive complex 2 components . PLOS ONE . 3 . 10 . e3404 . 2008 . 18852898 . 2561057 . 10.1371/journal.pone.0003404 . 2008PLoSO...3.3404J . free .
12. Sheldon CC, Rouse DT, Finnegan EJ, Peacock WJ, Dennis ES . The molecular basis of vernalization: the central role of FLOWERING LOCUS C (FLC) . Proceedings of the National Academy of Sciences of the United States of America . 97 . 7 . 3753–8 . March 2000 . 10716723 . 16312 . 10.1073/pnas.060023597 . free .