Roles of the Rlim-Rex1 axis during X chromosome inactivation in mice.

In female mice, the gene dosage from X chromosomes is adjusted by a process called X chromosome inactivation (XCI) that occurs in two steps. An imprinted form of XCI (iXCI) that silences the paternally inherited X chromosome (Xp) is initiated at the 2- to 4-cell stages. As extraembryonic cells including trophoblasts keep the Xp silenced, epiblast cells that give rise to the embryo proper reactivate the Xp and undergo a random form of XCI (rXCI) around implantation. Both iXCI and rXCI require the lncRNA Xist, which is expressed from the X to be inactivated. The X-linked E3 ubiquitin ligase Rlim (Rnf12) in conjunction with its target protein Rex1 (Zfp42), a critical repressor of Xist, have emerged as major regulators of iXCI. However, their roles in rXCI remain controversial. Investigating early mouse development, we show that the Rlim-Rex1 axis is active in pre-implantation embryos. Upon implantation Rex1 levels are downregulated independently of Rlim specifically in epiblast cells. These results provide a conceptual framework of how the functional dynamics between Rlim and Rex1 ensures regulation of iXCI but not rXCI in female mice.

Regulation of Mouse Retroelement MuERV-L/MERVL Expression by REX1 and Epigenetic Control of Stem Cell Potency.

About half of the mammalian genome is occupied by DNA sequences that originate from transposable elements. Retrotransposons can modulate gene expression in different ways and, particularly retrotransposon-derived long terminal repeats, profoundly shape expression of both surrounding and distant genomic loci. This is especially important in pre-implantation development, during which extensive reprograming of the genome takes place and cells pass through totipotent and pluripotent states. At this stage, the main mechanism responsible for retrotransposon silencing, i.e., DNA methylation, is inoperative. A particular retrotransposon called muERV-L/MERVL is expressed during pre-implantation stages and contributes to the plasticity of mouse embryonic stem cells. This review will focus on the role of MERVL-derived sequences as controlling elements of gene expression specific for pre-implantation development, two-cell stage-specific gene expression, and stem cell pluripotency, the epigenetic mechanisms that control their expression, and the contributions of the pluripotency marker REX1 and the related Yin Yang 1 family of transcription factors to this regulation process.