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.

Single-cell assessment of trophoblast stem cell-based organoids as human placenta-modeling platforms

“…Comparing in vivo and TOrg regulators of this process, we again confirm known transcripts (i.e., MSX2 56 ) important for syncytialization while identifying novel (i.e., PBX1 , TAF7 , ESRRA , ETV4 ) transcripts driving syncytialization in vivo and in vitro . However, because the placental syncytium represents a large, multinucleated, and diverse cell layer, these in silico differences may simply reflect the existence of distinct SCT subtypes found in vivo 57, 58 . As well, because TOrg polarity is inverted with an inner SCT layer, TOrg SCT artefacts may bias our single-cell findings.…”