Endogenous retrovirus MER50-derived enhancers confer the transcriptional regulation of human trophoblast syncytialization [ChIP-Seq]

Multinucleated syncytiotrophoblasts (STBs), which are in direct contact with maternal blood, constitute the maternal-fetal interface critical for nutrient allocation, hormone production and immunological modulation during pregnancy. However, the genetic and epigenetic regulatory mechanisms governing trophoblast syncytialization remain largely elusive. We delineate that endogenous retroviruses (ERVs), which have been exapted as regulatory sequences for specific functional adaptations in placenta, profoundly rewire transcriptional program of trophoblast syncytialization. Here, we first determined dynamic bivalent ERV-derived enhancers with dual occupancy of H3K9me3 and H3K27ac in human trophoblast stem cells (hTSCs), which emerge as cell specific regulators of gene expression with markedly resolved H3K9me3 during differentiation towards STBs. Of note, bivalent enhancers derived from the Simiiformes-specific MER50 transposons were linked to a cluster of STB-specific genes. Importantly, depletions of MER50 elements adjacent to several STB genes, including MFSD2A, TNFAIP2 and RAI14, significantly attenuated their expression concomitant to dysregulated syncytium formation. Together, we propose that ERV-derived enhancers, MER50 specifically, fine-tune the transcriptional program accounting for human trophoblast syncytialization, which sheds light on novel epigenetic regulatory mechanisms underlying placental development. Overall design: We generated ChIP-Seq and RNA-Seq data in this study. ChIP-Seq data are for H3K27ac, H3K4me3 in hTSC (human trophoblast stem cell) and differentiated STB(syncytiotrophoblast) at 24h, 48h. RNA-Seq data are for hTSC and STB at four time points: 24h, 48h, 72h, 96h.