Regulation of endogenous retrovirus-derived regulatory elements by GATA2/3 and MSX2 in human trophoblast stem cells (ChIP-seq)

The placenta is an organ with extraordinary phenotypic diversity in eutherian mammals. Recent evidence suggest that numerous human placental enhancers are evolved from lineage-specific insertions of endogenous retroviruses (ERVs), yet the transcription factors (TFs) underlying their regulation remain largely elusive. Here, by first focusing on MER41, a primate-specific ERV family previously linked to placenta and innate immunity, we uncover the binding motifs of multiple crucial trophoblast TFs (GATA2/3, MSX2, GRHL2) in addition to innate immuninty TFs STAT1 and IRF1. Integration of ChIP-Seq data confirms the binding of GATA2/3 and MSX2 on the majority of MER41-derived enhancers in human trophoblast stem cells (TSCs). Notably, the usb-family composition of MER41-derived enhancers that are active in human TSCs are distinct from those activated upon interferon stimulation, which is determined by the binding of trophoblast TFs. We further demonstrate that GATA2/3 and MSX2 have prevalent binding on numerous other ERV families – indicating their broad impact on ERV-derived placental enhancers. Functionally, the derepression of many syncytiotrophoblast genes after disruption of MSX2 is likely to be mediated by enhancers derived from ERVs – suggesting ERVs are also important for mediating transcriptional repression in human TSCs. Overall, this study characterized the prevalent binding of GATA2/3, MSX2 and their co-factors on ERV-derived enhancers in human TSCs and provided mechanistic insights into the importance of ERVs in human trophoblast regulatory network. ChIP-Seq (H3K27ac) and RNA-Seq data are generated for human trophoblast stem cells with or without interferon-gamma stimulation, respectively.