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Ectopic expression of DNMT3L in human trophoblast stem cells restores features of the placental methylome [ChIP-seq]

ABSTRACT: The placental DNA methylation landscape is unique, with widespread partially methylated domains (PMDs) and hundreds of placental-specific imprinted domains. Furthermore, the placental ‘methylome’ has been the focus of extensive study for links with pregnancy complications. Human trophoblast stem cells (hTSCs) offer exciting potential for functional epigenetic studies; however, whether the hTSC epigenome recapitulates primary cytotrophoblast, remains poorly described. In this study, we demonstrate that hTSCs exhibit an atypical methylome, with DNA methylation present over transcribed gene bodies but a complete loss of placental PMDs. Using single-cell RNA-seq from human embryogenesis, hTSCs display a notable absence of DNMT3L expression. Ectopic expression of DNMT3L in hTSCs restored placental PMDs. DNMT3L-expressing hTSCs showed comparable stemness but failed to syncytialise in organoid culture, associated with hypermethylation of STB transcription factor motifs. These findings reveal that DNMT3L is essential in establishing the human placental methylome and that DNMT3L downregulation is necessary for successful trophoblast differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266194 | GEO | 2025/01/08

REPOSITORIES: GEO

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Ectopic expression of DNMT3L in human trophoblast stem cells restores features of the placental methylome [RNA-seq]

Project description:The placental DNA methylation landscape is unique, with widespread partially methylated domains (PMDs) and hundreds of placental-specific imprinted domains. Furthermore, the placental ‘methylome’ has been the focus of extensive study for links with pregnancy complications. Human trophoblast stem cells (hTSCs) offer exciting potential for functional epigenetic studies; however, whether the hTSC epigenome recapitulates primary cytotrophoblast, remains poorly described. In this study, we demonstrate that hTSCs exhibit an atypical methylome, with DNA methylation present over transcribed gene bodies but a complete loss of placental PMDs. Using single-cell RNA-seq from human embryogenesis, hTSCs display a notable absence of DNMT3L expression. Ectopic expression of DNMT3L in hTSCs restored placental PMDs. DNMT3L-expressing hTSCs showed comparable stemness but failed to syncytialise in organoid culture, associated with hypermethylation of STB transcription factor motifs. These findings reveal that DNMT3L is essential in establishing the human placental methylome and that DNMT3L downregulation is necessary for successful trophoblast differentiation.

2025-01-08 | GSE266193 | GEO

Ectopic expression of DNMT3L in human trophoblast stem cells restores features of the placental methylome [PBAT BS-Seq]

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2023-08-03 | GSE229702 | GEO

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

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

2023-11-09 | GSE247035 | GEO

A genome-wide CRISPR-Cas9 knockout screen identifies essential and growth-restricting genes in human trophoblast stem cells

Project description:The recent derivation of bona fide human trophoblast stem cells (hTSCs) significantly improved our ability to study human placental biology and pathologies, but few studies have investigated the molecular regulators of hTSC identity. Therefore, we utilized a genome-wide CRISPR-Cas9 knockout screen to comprehensively define genes essential for or restricting the fitness of hTSCs. The resulting essential and growth-restricting genes include both well-established and potentially novel trophoblast regulators. We referenced our data to those of similar genetic screens performed in cancer cell lines and primed human pluripotent stem cells (hPSCs), as well as gene expression data of the early human embryos, to identify potential hTSC-specific and -enriched regulators. Among those are TEAD1, a gene previously reported to be dispensable for mouse placentation6. However, in the human trophoblast context, TEAD1 targets many hTSC regulators and plays a major role in its specification and maintenance. Overall, our study presents the first CRISPR/Cas9 knockout screen in a human extraembryonic lineage and provides a valuable resource for future trophoblast research.

2022-04-11 | GSE172329 | GEO

Naïve human embryonic stem cells can give rise to cells with trophoblast-like transcriptome and methylome [RNA-Seq]

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Naïve human embryonic stem cells can give rise to cells with trophoblast-like transcriptome and methylome [Bisulfite-Seq]

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