Dataset Information

Single-nucleus multi-omic profiling of human placental syncytiotrophoblasts identifies cellular trajectories during pregnancy [placenta-ncbi-cell-line_ChIPseq_cuttag]

ABSTRACT: The human placenta plays vital roles in ensuring a successful pregnancy. Despite the growing body of knowledge about its cellular compositions and functions, however, there has been limited research on the heterogeneity of the billions of nuclei within the syncytiotrophoblast (STB), a multinucleated entity primarily responsible for placental function. Here, we conducted integrated snRNA-seq and snATAC-seq on human placentas from early and late pregnancy. Our findings demonstrate the dynamic heterogeneity and developmental trajectories of STB nuclei and their presence in human trophoblast stem cells (hTSCs)-derived STB. Furthermore, we identified transcription factor (TF) motifs that are biased towards diverse STB nuclear lineages through their associated gene regulatory networks. The role of these TFs in STB differentiation were confirmed in the hTSCs- and trophoblast organoid-derived STB. Together, our data provide valuable insights into the heterogeneity of human STB and represents a valuable resource for interpreting its associated pregnancy complications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247035 | GEO | 2023/11/09

REPOSITORIES: GEO

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Project description:The outer surface of chorionic villi in the human placenta consists of a single multinucleated cell called the syncytiotrophoblast (STB). The unique cellular ultrastructure of the STB presents challenges in deciphering its gene expression signature at the single-cell level, as the STB contains billions of nuclei in a single cell. There are many gaps in understanding the molecular mechanisms and developmental trajectories involved in STB formation and differentiation. To identify the underlying control of the STB, we performed comparative single nucleus (SN) and single cell (SC) RNA sequencing on placental tissue and tissue-derived trophoblast organoids (TOs). We found that SN was essential to capture the STB population from both tissue and TOs. Differential gene expression and pseudotime analysis of TO-derived STB identified three distinct nuclear subtypes reminiscent of those recently identified in vivo. These included a juvenile nuclear population that exhibited both CTB and STB marker expression, a population enriched in genes involved in oxygen sensing, and finally a subtype enriched in transport and GTPase signaling molecules. Notably, suspension culture conditions of TOs that restore the native orientation of the STB (STBout) showed elevated expression of canonical STB markers and pregnancy hormones, along with a greater proportion of the STB nucleus subtype specializing in transport and GTPase signaling, compared to those cultivated with an inverted STB polarity (STBin). Gene regulatory analysis identified novel markers of STB differentiation conserved in tissue and TOs, including the chromatin remodeler RYBP, that exhibited STB-specific RNA and protein expression. CRISPR/Cas9 knock out of RYBP in STBin TOs did not affect cell-cell fusion, but bulk sequencing demonstrates the downregulation of the pregnancy hormone CSH1 and upregulation of many genes that define the oxygen sensing STB nuclear subtype. Finally, we compared STB gene expression signatures amongst first trimester tissue, full-term tissue, and TOs, identifying many commonalities but also notable variability across each sample type. This indicates that STB gene expression is responsive to its environmental context. Our findings emphasize the utility of TOs to accurately model STB differentiation and the distinct nuclear subtypes observed in vivo, offering a versatile platform for unraveling the molecular mechanisms governing STB functions in placental biology and disease. The processed datasets can be visualized online at https://gladfelterlab.shinyapps.io/PlacentaRNAsequencing/.