Biology:Polycomb recruitment in X chromosome inactivation

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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.

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.[25][26] 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.

References

  1. ↑ "X chromosome inactivation: when dosage counts". Cell 139 (5): 865–7. November 2009. doi:10.1016/j.cell.2009.11.009. PMID 19945374. 
  2. ↑ "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. 
  3. ↑ "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. 
  4. ↑ "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. 
  5. ↑ "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. 
  6. ↑ "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. 
  7. ↑ "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. 
  8. ↑ "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. 
  9. ↑ "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. 
  10. ↑ "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. 
  11. ↑ "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. 
  12. ↑ "Systematic discovery of Xist RNA binding proteins". Cell 161 (2): 404–16. April 2015. doi:10.1016/j.cell.2015.03.025. PMID 25843628. 
  13. ↑ "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. 
  14. ↑ "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. 
  15. ↑ "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. 
  16. ↑ "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. 
  17. ↑ "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. 
  18. ↑ "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. 
  19. ↑ "Long non-coding RNA-polycomb intimate rendezvous". Open Biology 10 (9): 200126. September 2020. doi:10.1098/rsob.200126. PMID 32898472. 
  20. ↑ "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. 
  21. ↑ "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. 
  22. ↑ "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. 
  23. ↑ "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. 
  24. ↑ "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. 
  25. ↑ 25.0 25.1 "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. 
  26. ↑ 26.0 26.1 26.2 "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. 
  27. ↑ Xist IncRNA forms silencing granules that induce heterochromatin formation and repressive complexes recruitment by phase separation. 2018-06-20. pp. 351015. doi:10.1101/351015. 
  28. ↑ "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. 



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