Retroviruses have been invading mammalian germlines for millions of years, accumulating in the form of endogenous retroviruses (ERVs) that account for nearly one-tenth of the mouse and human genomes. ERVs are epigenetically silenced during development, yet the cellular factors recognizing ERVs in a sequence-specific manner remain elusive. Here we demonstrate that ZFP809, a member of the Krüppel-associated box zinc finger protein (KRAB-ZFP) family, initiates the silencing of ERVs in a sequence-specific manner via recruitment of heterochromatin-inducing complexes. ZFP809 knockout mice display highly elevated levels of ZFP809-targeted ERVs in somatic tissues. ERV reactivation is accompanied by an epigenetic shift from repressive to active histone modifications but only slight destabilization of DNA methylation. Importantly, using conditional alleles and rescue experiments, we demonstrate that ZFP809 is required to initiate ERV silencing during embryonic development but becomes largely dispensable in somatic tissues. Finally, we show that the DNA-binding specificity of ZFP809 is evolutionarily conserved in the Muroidea superfamily of rodents and predates the endogenization of retroviruses presently targeted by ZFP809 in Mus musculus. In sum, these data provide compelling evidence that ZFP809 evolved to recognize foreign DNA and establish histone modification-based epigenetic silencing of ERVs.

Histone demethylase LSD1 can form complex with different Rcor family corepressors in different cell types. It remains unknown if cell-specific Rcor proteins function specifically in distinct cell types. Here, we report that Rcor2 is predominantly expressed in ESCs and forms a complex with LSD1 and facilitates its nucleosomal demethylation activity. Knockdown of Rcor2 in ESCs inhibited ESC proliferation and severely impaired the pluripotency. Moreover, knockdown of Rcor2 greatly impaired the formation of induced pluripotent stem (iPS) cells. In contrast, ectopic expression of Rcor2 in somatic cells together with Oct4, Sox2, and Klf4 promoted the formation of iPS cells. Most interestingly, ectopic expression of Rcor2 in both mouse and human somatic cells effectively substituted the requirement for exogenous Sox2 expression in somatic cell reprogramming. STEM CELLS 2011;

Epigenetic regulatory complexes play key roles in the modulation of transcriptional regulation underlying neural stem cell (NSC) proliferation and progeny specification. How specific cofactors guide histone demethylase LSD1/KDM1A complex to regulate distinct NSC-related gene activation and repression in cortical neurogenesis remains unclear. Here we demonstrate that Rcor2, a co-repressor of LSD1, is mainly expressed in the central nervous system (CNS) and plays a key role in epigenetic regulation of cortical development. Depletion of Rcor2 results in reduced NPC proliferation, neuron population, neocortex thickness and brain size. We find that Rcor2 directly targets Dlx2 and Shh, and represses their expressions in developing neocortex. In addition, inhibition of Shh signals rescues the neurogenesis defects caused by Rcor2 depletion both in vivo and in vitro. Hence, our findings suggest that co-repressor Rcor2 is critical for cortical development by repressing Shh signalling pathway in dorsal telencephalon.

Embryo viability relies on placental repression: The insulin-like growth factor (IGF) signaling pathway controls maternal supply of and fetal demands for nutrients. Yang et al. report that the essential KRAB–zinc finger protein ZFP568 specifically and directly represses a placental-specific IGF2 transcript during early mouse development. Elimination of ZFP568 in vivo leads to the inappropriate early activation of transcription, which results in embryonic death owing to overexpression of IGF2 peptide. Thus, the specific, targeted preimplantation repression of a promoter is essential for viability. Science , this issue p. 757