Polycomb recruitment in X chromosome inactivation explained

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]

Phases

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, is monoallelically upregulated[3] and it spreads in cis along the future inactive X (Xi), relocates to the nuclear periphery.[4] [5] [6] and recruits repressive chromatin-remodelling complexes[7] Among these, Xist recruits proteins of the Polycomb repressive complexes.[8] [9] Whether Xist directly recruits Polycomb repressive complex 2 (PRC2) to the chromatin[10] or this recruitment is the consequence of Xist-mediated changes on the chromatin has been object of intense debate.[11]

Mechanism

Some studies showed that PRC2 components are not associated with Xist RNA or do not interact functionally.[12] [13] [14] [15] However another study has shown by means of mass spectrometry analysis,[16] 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),[17] [18] supporting Xist-mediated recruitment of PRC2 to the X chromosome. However it is not clear whether such interactions occurs in vivo under physiological conditions.[19] 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,[20] while another showed that Xist and PRC2 are tightly linked.[21] It is possible that several mechanisms recruit PRC2 in parallel, including direct Xist-mediated recruitment, adaptor proteins, chromatin changes, RNA pol II exclusion, or PRC1 recruitment.[22] [23] For instance, PRC2 recruitment is linked to PRC1-mediated H2A119 ubiquitination in differentiating embryonic stem cells (ESCs).[24] [25] [26] where PRC1 recruitment is mediated by hnrnpK and Xist repB. In fully differentiated cells, PRC2 recruitment seems to be dependent on Xist RepA.[26] It is possible that alternative and complementary pathways such as phase separation [27] [28] 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 (https://en.wikipedia.org/wiki/Gian_Gaetano_Tartaglia)

Notes and References

  1. Nora EP, Heard E . X chromosome inactivation: when dosage counts . Cell . 139 . 5 . 865–7 . November 2009 . 19945374 . 10.1016/j.cell.2009.11.009 . free .
  2. Wutz A, Jaenisch R . A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation . Molecular Cell . 5 . 4 . 695–705 . April 2000 . 10882105 . 10.1016/s1097-2765(00)80248-8 . free .
  3. Cerase A, Young AN, Ruiz NB, Buness A, Sant GM, Arnold M, Di Giacomo M, Ascolani M, Kumar M, Hierholzer A, Trigiante G, Marzi SJ, Avner P . 6 . Chd8 regulates X chromosome inactivation in mouse through fine-tuning control of Xist expression . Communications Biology . 4 . 1 . 485 . April 2021 . 33859315 . 10.1038/s42003-021-01945-1 . 8050208 . free .
  4. Chen CK, Blanco M, Jackson C, Aznauryan E, Ollikainen N, Surka C, Chow A, Cerase A, McDonel P, Guttman M . 6 . Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing . Science . 354 . 6311 . 468–472 . October 2016 . 27492478 . 10.1126/science.aae0047 . 2016Sci...354..468C . free .
  5. Young AN, Perlas E, Ruiz-Blanes N, Hierholzer A, Pomella N, Martin-Martin B, Liverziani A, Jachowicz JW, Giannakouros T, Cerase A . 6 . 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 . 33846535 . 10.1038/s42003-021-01944-2 . 8041748 . free .
  6. Zhang LF, Huynh KD, Lee JT . 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 . 17512404 . 10.1016/j.cell.2007.03.036 . free .
  7. Chow J, Heard E . X inactivation and the complexities of silencing a sex chromosome . Current Opinion in Cell Biology . 21 . 3 . 359–66 . June 2009 . 19477626 . 10.1016/j.ceb.2009.04.012 .
  8. de Napoles M, Mermoud JE, Wakao R, Tang YA, Endoh M, Appanah R, Nesterova TB, Silva J, Otte AP, Vidal M, Koseki H, Brockdorff N . 6 . 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 . 15525528 . 10.1016/j.devcel.2004.10.005 . free .
  9. Plath K, Fang J, Mlynarczyk-Evans SK, Cao R, Worringer KA, Wang H, de la Cruz CC, Otte AP, Panning B, Zhang Y . 6 . Role of histone H3 lysine 27 methylation in X inactivation . Science . 300 . 5616 . 131–5 . April 2003 . 12649488 . 10.1126/science.1084274 . 2003Sci...300..131P . 28578313 . free .
  10. Zhao J, Sun BK, Erwin JA, Song JJ, Lee JT . Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome . Science . 322 . 5902 . 750–6 . October 2008 . 18974356 . 2748911 . 10.1126/science.1163045 . 2008Sci...322..750Z .
  11. 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 . 6 . 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 . 24469834 . 3926064 . 10.1073/pnas.1312951111 . 2014PNAS..111.2235C . free .
  12. Chu C, Zhang QC, da Rocha ST, Flynn RA, Bharadwaj M, Calabrese JM, Magnuson T, Heard E, Chang HY . 6 . Systematic discovery of Xist RNA binding proteins . Cell . 161 . 2 . 404–16 . April 2015 . 25843628 . 4425988 . 10.1016/j.cell.2015.03.025 . Howard Y. Chang .
  13. 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 . 6 . The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3 . Nature . 521 . 7551 . 232–6 . May 2015 . 25915022 . 4516396 . 10.1038/nature14443 . 2015Natur.521..232M .
  14. Moindrot B, Cerase A, Coker H, Masui O, Grijzenhout A, Pintacuda G, Schermelleh L, Nesterova TB, Brockdorff N . 6 . 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 . 26190105 . 4534822 . 10.1016/j.celrep.2015.06.053 .
  15. Monfort A, Di Minin G, Postlmayr A, Freimann R, Arieti F, Thore S, Wutz A . 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 . 26190100 . 4530576 . 10.1016/j.celrep.2015.06.067 .
  16. Minajigi A, Froberg J, Wei C, Sunwoo H, Kesner B, Colognori D, Lessing D, Payer B, Boukhali M, Haas W, Lee JT . 6 . Chromosomes. A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation . Science . 349 . 6245 . July 2015 . 26089354 . 4845908 . 10.1126/science.aab2276 .
  17. Cifuentes-Rojas C, Hernandez AJ, Sarma K, Lee JT . Regulatory interactions between RNA and polycomb repressive complex 2 . Molecular Cell . 55 . 2 . 171–85 . July 2014 . 24882207 . 4107928 . 10.1016/j.molcel.2014.05.009 .
  18. Davidovich C, Wang X, Cifuentes-Rojas C, Goodrich KJ, Gooding AR, Lee JT, Cech TR . Toward a consensus on the binding specificity and promiscuity of PRC2 for RNA . Molecular Cell . 57 . 3 . 552–8 . February 2015 . 25601759 . 4320675 . 10.1016/j.molcel.2014.12.017 .
  19. Cerase A, Tartaglia GG . Long non-coding RNA-polycomb intimate rendezvous . Open Biology . 10 . 9 . 200126 . September 2020 . 32898472 . 7536065 . 10.1098/rsob.200126 .
  20. Cerase A, Pintacuda G, Tattermusch A, Avner P . Xist localization and function: new insights from multiple levels . Genome Biology . 16 . 166 . August 2015 . 1 . 26282267 . 4539689 . 10.1186/s13059-015-0733-y . free .
  21. Sunwoo H, Wu JY, Lee JT . 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 . 26195790 . 4534268 . 10.1073/pnas.1503690112 . 2015PNAS..112E4216S . free .
  22. Pintacuda G, Cerase A . X Inactivation Lessons from Differentiating Mouse Embryonic Stem Cells . Stem Cell Reviews and Reports . 11 . 5 . 699–705 . October 2015 . 26198263 . 4561061 . 10.1007/s12015-015-9597-5 .
  23. Pinter SF . 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 . 27072488 . 10.1016/j.semcdb.2016.03.023 .
  24. Almeida M, Pintacuda G, Masui O, Koseki Y, Gdula M, Cerase A, Brown D, Mould A, Innocent C, Nakayama M, Schermelleh L, Nesterova TB, Koseki H, Brockdorff N . 6 . PCGF3/5-PRC1 initiates Polycomb recruitment in X chromosome inactivation . Science . 356 . 6342 . 1081–1084 . June 2017 . 28596365 . 6522364 . 10.1126/science.aal2512 . 2017Sci...356.1081A .
  25. Pintacuda G, Wei G, Roustan C, Kirmizitas BA, Solcan N, Cerase A, Castello A, Mohammed S, Moindrot B, Nesterova TB, Brockdorff N . 6 . 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 . 29220657 . 5735038 . 10.1016/j.molcel.2017.11.013 .
  26. Pintacuda G, Young AN, Cerase A . Function by Structure: Spotlights on Xist Long Non-coding RNA . Frontiers in Molecular Biosciences . 4 . 90 . 2017 . 29302591 . 5742192 . 10.3389/fmolb.2017.00090 . free .
  27. Cerase A, Armaos A, Cid F, Avner P, Tartaglia GG . 2018-06-20. Xist IncRNA forms silencing granules that induce heterochromatin formation and repressive complexes recruitment by phase separation . 351015. 10.1101/351015. free.
  28. Cerase A, Armaos A, Neumayer C, Avner P, Guttman M, Tartaglia GG . Phase separation drives X-chromosome inactivation: a hypothesis . Nature Structural & Molecular Biology . 26 . 5 . 331–334 . May 2019 . 31061525 . 10.1038/s41594-019-0223-0 . 11573/1279455 . 146112261 . free .

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