Biology:Polycomb-group proteins

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Short description: Family of proteins that play a role in chromatin remodeling

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 (p16Ink4a, p19Arf).[4][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]

Recruitment in X chromosome inactivation

X chromosome inactivation (XCI) is the phenomenon that has been selected during the evolution to balance X-linked gene dosage between XX females and XY males.[9] It is can be divided into two phases: the establishment phase when gene silencing is reversible, and maintenance phase when gene silencing becomes irreversible.[10] During the establishment phase XCI, Xist RNA, the master regulator of this process, is monoallelically upregulated,[11] and it spreads in cis along the future inactive X (Xi), relocating to the nuclear periphery.[12][13][14] and recruits repressive chromatin-remodelling complexes,[15] including proteins of the polycomb repressive complexes.[16][17] Whether Xist directly recruits polycomb repressive complex 2 (PRC2) to the chromatin[18] or this recruitment is the consequence of Xist-mediated changes on the chromatin has been the object of intense debate.[19]

Mechanism

One super resolution study showed that Xist and PRC2 do not directly interact (above), a second study that they are tightly and statistically significantly linked.

Some studies showed that PRC2 components are not associated with Xist RNA or do not interact functionally.[20][21][22][23] Another has shown, by means of mass spectrometry analysis,[24] that two subunits of PRC2 may interact with Xist, although these proteins are also found in other complexes and are not unique components of the PRC2 complex.

PRC2 binds the A-repeat (RepA) of Xist RNA directly and with very high affinity (dissociation constants of 10-100 nanomolar),[25][26] supporting Xist-mediated recruitment of PRC2 to the X chromosome. It is unclear if such interactions occurs in vivo under physiological conditions.[27] Failure to turn up PRC2 proteins in function screens may result from incomplete screens or because cells cannot survive or compete without PRC2. Two super-resolution microscopy analyses have presented divergent views: one showed that Xist and PRC2 are spatially separated,[28] the other that Xist and PRC2 are tightly linked.[29] Recruitment of PCR could occur through several mechanisms in parallel, including direct Xist-mediated recruitment, adaptor proteins, chromatin changes, RNA pol II exclusion, or PRC1 recruitment.[30][31] For instance, PRC2 recruitment is linked to PRC1-mediated H2A119 ubiquitination in differentiating embryonic stem cells (ESCs).[32][33][34] where PRC1 recruitment is mediated by hnrnpK and Xist repB.[33][34] In fully differentiated cells, PRC2 recruitment seems to be dependent on Xist RepA.[34] Alternative and complementary pathways, such as phase separation,[35][36] could also be at work to establish PRC2 recruitment on the X in different experimental systems and during different stages of development. See also work from the Tartaglia lab.

In plants

The Polycomb gene FIE is expressed (blue) in unfertilised egg cells of the moss Physcomitrella patens (right) and expression ceases after fertilisation in the developing diploid sporophyte (left). In situ GUS staining of two female sex organs (archegonia) of a transgenic plant expressing a translational fusion of FIE-uidA under control of the native FIE promoter

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.[37] 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.[38]

Polycomb-group proteins also intervene in the control of flowering by silencing the Flowering Locus C gene.[39] 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.[40]

See also

References

  1. ↑ Morris KV, ed (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. pp. 29–44. ISBN 978-1-904455-25-7. https://books.google.com/books?id=r67Lrf9r9XEC&pg=PA29. 
  2. ↑ "Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains". PLOS Genetics 4 (10). October 2008. doi:10.1371/journal.pgen.1000242. PMID 18974828. 
  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. ↑ 4.0 4.1 "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. doi:10.1101/gad.1299505. PMID 15964994. 
  5. ↑ "Bmi1, stem cells, and senescence regulation". The Journal of Clinical Investigation 113 (2): 175–9. January 2004. doi:10.1172/JCI20800. PMID 14722607. 
  6. ↑ "Polycomb group genes: keeping stem cell activity in balance". PLOS Biology 6 (4). April 2008. doi:10.1371/journal.pbio.0060113. PMID 18447587. 
  7. ↑ "Epigenetic regulation of the INK4b-ARF-INK4a locus: in sickness and in health" (PDF). Epigenetics 5 (8): 685–90. 2010. doi:10.4161/epi.5.8.12996. PMID 20716961. PMC 3052884. http://www.landesbioscience.com/journals/epigenetics/article/12996/?nocache=2141572894. 
  8. ↑ "Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin". Nature Genetics 49 (2): 282–288. February 2017. doi:10.1038/ng.3735. PMID 27941795. 
  9. ↑ "X chromosome inactivation: when dosage counts". Cell 139 (5): 865–7. November 2009. doi:10.1016/j.cell.2009.11.009. PMID 19945374. 
  10. ↑ "A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation". Molecular Cell 5 (4): 695–705. April 2000. doi:10.1016/s1097-2765(00)80248-8. PMID 10882105. 
  11. ↑ "Chd8 regulates X chromosome inactivation in mouse through fine-tuning control of Xist expression". Communications Biology 4 (1): 485. April 2021. doi:10.1038/s42003-021-01945-1. PMID 33859315. 
  12. ↑ "Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing". Science 354 (6311): 468–472. October 2016. doi:10.1126/science.aae0047. PMID 27492478. Bibcode: 2016Sci...354..468C. 
  13. ↑ "Deletion of LBR N-terminal domains recapitulates Pelger-Huet anomaly phenotypes in mouse without disrupting X chromosome inactivation". Communications Biology 4 (1): 478. April 2021. doi:10.1038/s42003-021-01944-2. PMID 33846535. 
  14. ↑ "Perinucleolar targeting of the inactive X during S phase: evidence for a role in the maintenance of silencing". Cell 129 (4): 693–706. May 2007. doi:10.1016/j.cell.2007.03.036. PMID 17512404. 
  15. ↑ "X inactivation and the complexities of silencing a sex chromosome". Current Opinion in Cell Biology 21 (3): 359–66. June 2009. doi:10.1016/j.ceb.2009.04.012. PMID 19477626. 
  16. ↑ "Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation". Developmental Cell 7 (5): 663–76. November 2004. doi:10.1016/j.devcel.2004.10.005. PMID 15525528. 
  17. ↑ "Role of histone H3 lysine 27 methylation in X inactivation". Science 300 (5616): 131–5. April 2003. doi:10.1126/science.1084274. PMID 12649488. Bibcode: 2003Sci...300..131P. 
  18. ↑ "Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome". Science 322 (5902): 750–6. October 2008. doi:10.1126/science.1163045. PMID 18974356. Bibcode: 2008Sci...322..750Z. 
  19. ↑ "Spatial separation of Xist RNA and polycomb proteins revealed by superresolution microscopy". Proceedings of the National Academy of Sciences of the United States of America 111 (6): 2235–40. February 2014. doi:10.1073/pnas.1312951111. PMID 24469834. Bibcode: 2014PNAS..111.2235C. 
  20. ↑ "Systematic discovery of Xist RNA binding proteins". Cell 161 (2): 404–16. April 2015. doi:10.1016/j.cell.2015.03.025. PMID 25843628. 
  21. ↑ "The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3". Nature 521 (7551): 232–6. May 2015. doi:10.1038/nature14443. PMID 25915022. Bibcode: 2015Natur.521..232M. 
  22. ↑ "A Pooled shRNA Screen Identifies Rbm15, Spen, and Wtap as Factors Required for Xist RNA-Mediated Silencing". Cell Reports 12 (4): 562–72. July 2015. doi:10.1016/j.celrep.2015.06.053. PMID 26190105. 
  23. ↑ "Identification of Spen as a Crucial Factor for Xist Function through Forward Genetic Screening in Haploid Embryonic Stem Cells". Cell Reports 12 (4): 554–61. July 2015. doi:10.1016/j.celrep.2015.06.067. PMID 26190100. 
  24. ↑ "Chromosomes. A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation". Science 349 (6245). July 2015. doi:10.1126/science.aab2276. PMID 26089354. 
  25. ↑ "Regulatory interactions between RNA and polycomb repressive complex 2". Molecular Cell 55 (2): 171–85. July 2014. doi:10.1016/j.molcel.2014.05.009. PMID 24882207. 
  26. ↑ "Toward a consensus on the binding specificity and promiscuity of PRC2 for RNA". Molecular Cell 57 (3): 552–8. February 2015. doi:10.1016/j.molcel.2014.12.017. PMID 25601759. 
  27. ↑ "Long non-coding RNA-polycomb intimate rendezvous". Open Biology 10 (9). September 2020. doi:10.1098/rsob.200126. PMID 32898472. 
  28. ↑ "Xist localization and function: new insights from multiple levels". Genome Biology 16 (1): 166. August 2015. doi:10.1186/s13059-015-0733-y. PMID 26282267. 
  29. ↑ "The Xist RNA-PRC2 complex at 20-nm resolution reveals a low Xist stoichiometry and suggests a hit-and-run mechanism in mouse cells". Proceedings of the National Academy of Sciences of the United States of America 112 (31): E4216-25. August 2015. doi:10.1073/pnas.1503690112. PMID 26195790. Bibcode: 2015PNAS..112E4216S. 
  30. ↑ "X Inactivation Lessons from Differentiating Mouse Embryonic Stem Cells". Stem Cell Reviews and Reports 11 (5): 699–705. October 2015. doi:10.1007/s12015-015-9597-5. PMID 26198263. 
  31. ↑ "A Tale of Two Cities: How Xist and its partners localize to and silence the bicompartmental X". Seminars in Cell & Developmental Biology 56: 19–34. August 2016. doi:10.1016/j.semcdb.2016.03.023. PMID 27072488. 
  32. ↑ "PCGF3/5-PRC1 initiates Polycomb recruitment in X chromosome inactivation". Science 356 (6342): 1081–1084. June 2017. doi:10.1126/science.aal2512. PMID 28596365. Bibcode: 2017Sci...356.1081A. 
  33. ↑ 33.0 33.1 "hnRNPK Recruits PCGF3/5-PRC1 to the Xist RNA B-Repeat to Establish Polycomb-Mediated Chromosomal Silencing". Molecular Cell 68 (5): 955–969.e10. December 2017. doi:10.1016/j.molcel.2017.11.013. PMID 29220657. 
  34. ↑ 34.0 34.1 34.2 "Function by Structure: Spotlights on Xist Long Non-coding RNA". Frontiers in Molecular Biosciences 4: 90. 2017. doi:10.3389/fmolb.2017.00090. PMID 29302591. 
  35. ↑ "Xist IncRNA forms silencing granules that induce heterochromatin formation and repressive complexes recruitment by phase separation". bioRxiv. 2018-06-20. doi:10.1101/351015. 
  36. ↑ "Phase separation drives X-chromosome inactivation: a hypothesis". Nature Structural & Molecular Biology 26 (5): 331–334. May 2019. doi:10.1038/s41594-019-0223-0. PMID 31061525. 
  37. ↑ "Regulation of stem cell maintenance by the Polycomb protein FIE has been conserved during land plant evolution". Development 136 (14): 2433–44. July 2009. doi:10.1242/dev.035048. PMID 19542356. 
  38. ↑ "CHD3 proteins and polycomb group proteins antagonistically determine cell identity in Arabidopsis". PLOS Genetics 5 (8). August 2009. doi:10.1371/journal.pgen.1000605. PMID 19680533. 
  39. ↑ "Repression of FLOWERING LOCUS C and FLOWERING LOCUS T by the Arabidopsis Polycomb repressive complex 2 components". PLOS ONE 3 (10). 2008. doi:10.1371/journal.pone.0003404. PMID 18852898. Bibcode: 2008PLoSO...3.3404J. 
  40. ↑ "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. doi:10.1073/pnas.060023597. PMID 10716723. 

Further reading



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