Integrative snRNA-seq and snATAC-seq profiling revealed the dynamic nuclear heterogeneity and lineage-specific regulatory architecture of the human placental syncytiotrophoblast

Abstract The significance of the placenta in success pregnancy outcome has been generally acknowledged. Despite our growing understanding of placenta cellular compositions and function, the heterogeneity among billions of nuclei within the syncytiotrophoblast (STB), a multinucleated entity primarily responsible for placental function, remains largely understudied. To better understand the identity of nuclei within STB, we applied integrated single-nucleus RNA-seq (snRNA-seq) and single-nucleus sequencing assay for transposase-accessible chromatin (snATAC-seq) on human placentas at early and late pregnancy. We inferred dynamic STB nuclear-heterogeneity, lineage-determining enhancer gene-regulatory networks and differentiation trajectories of STB nuclei and revealed their crucial biological features. Intriguingly, we found that nascent STB nuclei were involved in diverse biosynthetic processes that might be coordinated by MAPK and Erbb siganling cascades, and STBFLT1 represented mature nuclei exhibited high expression of genes associated with oxygen response and extracellular matrix organization. Gene expression in STBPAPPA represented ones was associated with a wide variety of hormone production. We identified mature lineage biased master TFs such as JUNB and STAT5A. Through STAT5A deletion in the hTSCs, we verified the regulatory roles of it in down-regulation of STBPAPPA nucear associated gene expressions. Our data paves the way for charting human STB development and its related diseases.