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Polycomb recruitment in X chromosome inactivation

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Recruitment of Polycomb proteins 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[1]. XCI is usually divided in two phases, the establishment phase when gene silencing is reversible, and maintenance phase when gene silencing becomes irreversible[2]. During the establishment phase of X Chromosome Inactivation (XCI), Xist RNA, the master regulator of this process, spreads in cis along the future inactive X (Xi) and recruits repressive chromatin-remodelling complexes[3]. Among these, Xist recruits proteins of the Polycomb repressive complexes[4][5]. Whether Xist directly recruits Polycomb repressive complex 2 (PRC2) to the chromatin[6] or this recruitment is the consequence of Xist-mediated changes on the chromatin has been object of intense debate[7]. Among recent analyses of Xist interacting proteins[8][9][10][11][12], PRC2 components were not found to be associated with Xist RNA. One study however, showed by mass spectrometry[13], that two subunits of PRC2 may interact with Xist , although these proteins are are also found in other complexes and are not unique components of the PRC2 complex. Biochemical studies have also shown that in vitro PRC2 binds the A-repeat of Xist RNA directly and with very high affinity (dissociation constants of 10-100 nanomolar),[14][15] supporting Xist-mediated recruitment of PRC2 to the X chromosome. However it is not clear whether such interactions occurs in vivo under physiological conditions. Failure to turn up PRC2 proteins in function screens may be due to cells not being able to survive or compete without PRC2 or incomplete screens. Two super resolution microscopy analyses have presented different views from each other. One showed that Xist and PRC2 are spatially separated[16], while another showed that Xist and PRC2 are tightly linked[17]. It is possible that several mechanisms recruit PRC2 together, including Xist RNA, an adaptor protein, chromatin changes, RNA pol II exclusion, or PRC1 recruitment[18][19]. Recent paper from the Brockdorff lab showed that PRC2 recruitment is linked to PRC1-mediated H2A119ubiquitination in differentiating embryonic stem cells (ES)[20][21][22], where PRC1 recruitment is mediated by hnrnpK and Xist repB [21][22]. It is possible that alternative pathways (e.g. Xist RepA-dependent are needed in fully differentiated cells). More studies are needed to clarify the discrepancies between these observations.

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

References

  1. ^ Nora, EP; Heard, E (25 November 2009). "X chromosome inactivation: when dosage counts". Cell. 139 (5): 865–7. doi:10.1016/j.cell.2009.11.009. PMID 19945374.
  2. ^ Wutz, A; Jaenisch, R (April 2000). "A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation". Molecular Cell. 5 (4): 695–705. doi:10.1016/s1097-2765(00)80248-8. PMID 10882105.
  3. ^ Chow, J; Heard, E (June 2009). "X inactivation and the complexities of silencing a sex chromosome". Current Opinion in Cell Biology. 21 (3): 359–66. doi:10.1016/j.ceb.2009.04.012. PMID 19477626.
  4. ^ de Napoles, Mariana; Mermoud, Jacqueline E.; Wakao, Rika; Tang, Y. Amy; Endoh, Mitusuhiro; Appanah, Ruth; Nesterova, Tatyana B.; Silva, Jose; Otte, Arie P.; Vidal, Miguel; Koseki, Haruhiko; Brockdorff, Neil (1 November 2004). "Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation". Developmental Cell. 7 (5): 663–676. doi:10.1016/j.devcel.2004.10.005. ISSN 1534-5807. PMID 15525528.
  5. ^ Plath, Kathrin; Fang, Jia; Mlynarczyk-Evans, Susanna K.; Cao, Ru; Worringer, Kathleen A.; Wang, Hengbin; de la Cruz, Cecile C.; Otte, Arie P.; Panning, Barbara; Zhang, Yi (4 April 2003). "Role of histone H3 lysine 27 methylation in X inactivation". Science. 300 (5616): 131–135. doi:10.1126/science.1084274. ISSN 1095-9203. PMID 12649488.
  6. ^ Zhao, J; Sun, BK; Erwin, JA; Song, JJ; Lee, JT (31 October 2008). "Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome". Science. 322 (5902): 750–6. doi:10.1126/science.1163045. PMC 2748911. PMID 18974356.
  7. ^ Cerase, A; Smeets, D; Tang, YA; Gdula, M; Kraus, F; Spivakov, M; Moindrot, B; Leleu, M; Tattermusch, A; Demmerle, J; Nesterova, TB; Green, C; Otte, AP; Schermelleh, L; Brockdorff, N (11 February 2014). "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. doi:10.1073/pnas.1312951111. PMC 3926064. PMID 24469834.
  8. ^ Chu, C; Zhang, QC; da Rocha, ST; Flynn, RA; Bharadwaj, M; Calabrese, JM; Magnuson, T; Heard, E; Chang, HY (9 April 2015). "Systematic discovery of Xist RNA binding proteins". Cell. 161 (2): 404–16. doi:10.1016/j.cell.2015.03.025. PMC 4425988. PMID 25843628.
  9. ^ Minajigi, A; Froberg, JE; Wei, C; Sunwoo, H; Kesner, B; Colognori, D; Lessing, D; Payer, B; Boukhali, M; Haas, W; Lee, JT (17 July 2015). "Chromosomes. A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation". Science. 349 (6245). doi:10.1126/science.aab2276. PMC 4845908. PMID 26089354.
  10. ^ McHugh, CA; Chen, CK; Chow, A; Surka, CF; Tran, C; McDonel, P; Pandya-Jones, A; Blanco, M; Burghard, C; Moradian, A; Sweredoski, MJ; Shishkin, AA; Su, J; Lander, ES; Hess, S; Plath, K; Guttman, M (14 May 2015). "The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3". Nature. 521 (7551): 232–6. doi:10.1038/nature14443. PMC 4516396. PMID 25915022.
  11. ^ Moindrot, B; Cerase, A; Coker, H; Masui, O; Grijzenhout, A; Pintacuda, G; Schermelleh, L; Nesterova, TB; Brockdorff, N (28 July 2015). "A Pooled shRNA Screen Identifies Rbm15, Spen, and Wtap as Factors Required for Xist RNA-Mediated Silencing". Cell reports. 12 (4): 562–72. doi:10.1016/j.celrep.2015.06.053. PMC 4534822. PMID 26190105.
  12. ^ Monfort, A; Di Minin, G; Postlmayr, A; Freimann, R; Arieti, F; Thore, S; Wutz, A (28 July 2015). "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. doi:10.1016/j.celrep.2015.06.067. PMC 4530576. PMID 26190100.
  13. ^ Minajigi, Anand; Froberg, John; Wei, Chunyao; Sunwoo, Hongjae; Kesner, Barry; Colognori, David; Lessing, Derek; Payer, Bernhard; Boukhali, Myriam (2015-07-17). "A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation". Science. 349 (6245). doi:10.1126/science.aab2276. ISSN 0036-8075. PMC 4845908. PMID 26089354.
  14. ^ Cifuentes-Rojas, Catherine; Hernandez, Alfredo J.; Sarma, Kavitha; Lee, Jeannie T. (2014-07-17). "Regulatory interactions between RNA and Polycomb Repressive Complex 2". Molecular Cell. 55 (2): 171–185. doi:10.1016/j.molcel.2014.05.009. ISSN 1097-2765. PMC 4107928. PMID 24882207.
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  17. ^ Sunwoo, Hongjae; Wu, John Y.; Lee, Jeannie T. (2015-08-04). "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): E4216–4225. doi:10.1073/pnas.1503690112. ISSN 1091-6490. PMC 4534268. PMID 26195790.
  18. ^ Pintacuda, G; Cerase, A (October 2015). "X Inactivation Lessons from Differentiating Mouse Embryonic Stem Cells". Stem cell reviews. 11 (5): 699–705. doi:10.1007/s12015-015-9597-5. PMC 4561061. PMID 26198263.
  19. ^ Pinter, SF (9 April 2016). "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. doi:10.1016/j.semcdb.2016.03.023. PMID 27072488.
  20. ^ Almeida, Mafalda; Pintacuda, Greta; Masui, Osamu; Koseki, Yoko; Gdula, Michal; Cerase, Andrea; Brown, David; Mould, Arne; Innocent, Cassandravictoria (06 09, 2017). "PCGF3/5-PRC1 initiates Polycomb recruitment in X chromosome inactivation". Science (New York, N.Y.). 356 (6342): 1081–1084. doi:10.1126/science.aal2512. ISSN 1095-9203. PMID 28596365. {{cite journal}}: Check date values in: |date= (help)
  21. ^ a b Pintacuda, Greta; Wei, Guifeng; Roustan, Chloë; Kirmizitas, Burcu Anil; Solcan, Nicolae; Cerase, Andrea; Castello, Alfredo; Mohammed, Shabaz; Moindrot, Benoît (2017-12-07). "hnRNPK Recruits PCGF3/5-PRC1 to the Xist RNA B-Repeat to Establish Polycomb-Mediated Chromosomal Silencing". Molecular Cell. 68 (5): 955–969.e10. doi:10.1016/j.molcel.2017.11.013. ISSN 1097-4164. PMC 5735038. PMID 29220657.{{cite journal}}: CS1 maint: PMC format (link)
  22. ^ a b Pintacuda, Greta; Young, Alexander N.; Cerase, Andrea (2017). "Function by Structure: Spotlights on Xist Long Non-coding RNA". Frontiers in Molecular Biosciences. 4: 90. doi:10.3389/fmolb.2017.00090. ISSN 2296-889X. PMC 5742192. PMID 29302591.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
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