Polycomb 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.[1]

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.

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] Some studies showed that PRC2 components are not associated with Xist RNA or do not interact functionally.[8][9][10][11] However another study has shown by means of mass spectrometry analysis,[12] 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.

Biochemical studies have also shown that in vitro PRC2 binds the A-repeat (RepA) of Xist RNA directly and with very high affinity (dissociation constants of 10-100 nanomolar),[13][14] 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,[15] while another showed that Xist and PRC2 are tightly linked.[16] 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.[17][18] For instance, PRC2 recruitment is linked to PRC1-mediated H2A119 ubiquitination in differentiating embryonic stem cells (ESCs).[19][20][21] where PRC1 recruitment is mediated by hnrnpK and Xist repB.[20][21] In fully differentiated cells, PRC2 recruitment seems to be dependent on Xist RepA.[21] It is possible that alternative and complementary pathways such as phase separation [22][23] work to establish PRC2 recruitment on the X in different experimental systems and during different stages of development.

References
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  6. Zhao J, Sun BK, Erwin JA, Song JJ, Lee JT (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.
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  12. Minajigi A, Froberg J, Wei C, Sunwoo H, Kesner B, Colognori D, Lessing D, Payer B, Boukhali M, Haas W, Lee JT (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.
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  16. Sunwoo H, Wu JY, Lee JT (August 2015). "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. doi:10.1073/pnas.1503690112. PMC 4534268. PMID 26195790.
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