The 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). 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 subfamily compositions. We further demonstrate that GATA2/3 and MSX2 have prevalent binding to numerous other ERV families — indicating their broad impact on ERV-derived enhancers. Functionally, the derepression of many syncytiotrophoblast genes after MSX2 knockdown is likely to be mediated by regulatory elements derived from ERVs — suggesting ERVs are also important for mediating transcriptional repression. Overall, this study characterizes the regulation of ERV-derived regulatory elements by GATA2/3, MSX2, and their cofactors in human TSCs, and provides mechanistic insights into the importance of ERVs in human trophoblast regulatory network.

中文翻译：

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GATA2/3 和 MSX2 在人滋养层干细胞中对内源性逆转录病毒衍生调节元件的调节

胎盘是真兽类哺乳动物中具有非凡表型多样性的器官。最近的证据表明，许多人类胎盘增强子是从内源性逆转录病毒（ERV）的谱系特异性插入进化而来的，但其调节背后的转录因子（TF）在很大程度上仍然难以捉摸。在这里，通过首先关注 MER41（一个先前与胎盘和先天免疫相关的灵长类特异性 ERV 家族），我们发现了除了先天免疫 TF STAT1 和 IRF1 之外的多个关键滋养层 TF（GATA2/3、MSX2、GRHL2）的结合基序。ChIP-seq 数据的整合证实了 GATA2/3、MSX2 及其相关因子与人滋养层干细胞 (TSC) 中大多数 MER41 衍生增强子的结合。在人 TSC 中具有组成型活性的 MER41 衍生增强子与干扰素刺激后激活的增强子不同，这是由相关 TF 及其亚家族组成的结合决定的。我们进一步证明 GATA2/3 和 MSX2 与许多其他 ERV 家族具有普遍的结合——表明它们对 ERV 衍生的增强子具有广泛的影响。从功能上讲，MSX2 敲低后许多合体滋养层基因的去抑制很可能是由 ERV 衍生的调节元件介导的，这表明 ERV 对于介导转录抑制也很重要。总体而言，本研究描述了人类 TSC 中 GATA2/3、MSX2 及其辅助因子对 ERV 衍生调节元件的调节，并提供了有关 ERV 在人类滋养层调节网络中重要性的机制见解。