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
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.
