Prevalent regulation of GATA2/3 and MSX2 on endogenous retrovirus-derived regulatory elements in human trophoblast stem cells

crossref(2022)

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摘要
AbstractThe placenta is an organ with extraordinary phenotypic diversity in eutherian mammals. Recent evidence suggests 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 immunity TFs STAT1 and IRF1. Integration of ChIP-Seq data confirms the binding of GATA2/3, MSX2 and their related factors on the majority of MER41-derived enhancers in human trophoblast stem cells (TSCs). Notably, MER41-derived enhancers that are constitutively active in human TSCs are distinct from those activated upon interferon stimulation, which is determined by the binding of relevant TFs and their sub-family compositions. We further demonstrate that GATA2/3 and MSX2 have prevalent binding on numerous other ERV families – indicating their broad impact on ERV-derived enhancers. Functionally, the derepression of many syncytiotrophoblast genes after disruption of MSX2 is likely to be mediated by regulatory elements derived from ERVs – suggesting ERVs are also important for mediating transcriptional repression. Overall, this study characterized the prevalent regulation of GATA2/3, MSX2 and their co-factors on ERV-derived regulatory elements in human TSCs and provided mechanistic insights into the importance of ERVs in human trophoblast regulatory network.
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