Rex1/Zfp42 is a Yy1-related zinc-finger protein whose expression is frequently used to identify pluripotent stem cells. We show that depletion of Rex1 levels notably affected self-renewal of mouse embryonic stem (ES) cells in clonal assays, in the absence of evident differences in expression of marker genes for pluripotency or differentiation. By contrast, marked differences in expression of several endogenous retroviral elements (ERVs) were evident upon Rex1 depletion. We demonstrate association of REX1 to specific elements in chromatin-immunoprecipitation assays, most strongly to muERV-L and to a lower extent to IAP and musD elements. Rex1 regulates muERV-L expression in vivo, as we show altered levels upon transient gain-and-loss of Rex1 function in pre-implantation embryos. We also find REX1 can associate with the lysine-demethylase LSD1/KDM1A, suggesting they act in concert. Similar to REX1 binding to retrotransposable elements (REs) in ES cells, we also detected binding of the REX1 related proteins YY1 and YY2 to REs, although the binding preferences of the two proteins were slightly different. Altogether, we show that Rex1 regulates ERV expression in mouse ES cells and during pre-implantation development and suggest that Rex1 and its relatives have evolved as regulators of endogenous retroviral transcription.

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.