The Polycomb Group Protein EED Is Dispensable for the Initiation of Random X-Chromosome Inactivation

Open Access
Publisher Website
Google Scholar
Abstract
The Polycomb group (PcG) proteins are thought to silence gene expression by modifying chromatin. The Polycomb repressive complex 2 (PRC2) plays an essential role in mammalian X-chromosome inactivation (XCI), a model system to investigate heritable gene silencing. In the mouse, two different forms of XCI occur. In the preimplantation embryo, all cells undergo imprinted inactivation of the paternal X-chromosome (Xp). During the peri-implantation period, cells destined to give rise to the embryo proper erase the imprint and randomly inactivate either the maternal X-chromosome or the Xp; extraembryonic cells, on the other hand, maintain imprinted XCI of the Xp. PRC2 proteins are enriched on the inactive-X during early stages of both imprinted and random XCI. It is therefore thought that PRC2 contributes to the initiation of XCI. Mouse embryos lacking the essential PRC2 component EED harbor defects in the maintenance of imprinted XCI in differentiating trophoblast cells. Assessment of PRC2 requirement in the initiation of XCI, however, has been hindered by the presence of maternally derived proteins in the early embryo. Here we show that Eed−/− embryos initiate and maintain random XCI despite lacking any functional EED protein prior to the initiation of random XCI. Thus, despite being enriched on the inactive X-chromosome, PcGs appear to be dispensable for the initiation and maintenance of random XCI. These results highlight the lineage- and differentiation state–specific requirements for PcGs in XCI and argue against PcG function in the formation of the facultative heterochromatin of the inactive X-chromosome. During the development of an embryo, an equal population of cells gives rise to different tissues and organs and this occurs via the activation and silencing of different sets of genes. The Polycomb group (PcG) proteins are required for silencing genes for proper development. PcGs play an important role in silencing of one of the two X-chromosomes in female mammals. XX females inactivate one X-chromosome to equalize X-linked gene dosage to that of XY males. X-chromosome inactivation (XCI) is established in cells of the early embryo and when these cells divide they maintain silencing of the same X-chromosome. XCI, therefore, is a model system to understand long-term gene regulation. Here the authors test whether PcGs help initiate XCI by examining mouse embryos lacking the essential PcG protein EED. Their results show that XCI in embryonic cells occurs normally despite lacking EED. PcGs therefore are not required to initiate or maintain XCI in embryonic cells. The findings shed light on the specific requirements for PcGs in XCI and argue against a general silencing function for PcGs in XCI.