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RNA-seq analysis of EP300 and CREBBP knockdown in human trophoblast stem cells and extravillous trophoblasts

ABSTRACT: EP300 is known to be an important regulator of human trophoblast stem cell differentiation toward the extravillous trophoblast (EVT) lineage. To examine how EP300 affects gene expression in both TSCs and EVTs, and to compare these effects with those of its closely related paralog CREBBP, we performed RNA sequencing after siRNA-mediated knockdown. This dataset provides a useful transcriptional resource for understanding how EP300 and CREBBP contribute to trophoblast stem cell maintenance and EVT differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE336656 | GEO | 2026/08/25

REPOSITORIES: GEO

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Project description:Early placenta development involves cytotrophoblast differentiation into extravillous trophoblast (EVT) and syncytiotrophoblast (STB). Defective trophoblast development and function may result in severe pregnancy complications, including fetal growth restriction and pre-eclampsia. The incidence of these complications is increased in pregnancies of fetuses affected by Rubinstein–Taybi syndrome, a developmental disorder predominantly caused by heterozygous mutations in CREB-binding protein (CREBBP) or E1A-binding protein p300 (EP300). Although the acetyltransferases CREBBP and EP300 are paralogs with many overlapping functions, the increased incidence of pregnancy complications is specific for EP300 mutations. We hypothesized that these complications have their origin in early placentation and that EP300 is involved in that process. Therefore, we investigated the role of EP300 and CREBBP in trophoblast differentiation, using human trophoblast stem cells (TSCs) and trophoblast organoids. We found that pharmacological CREBBP/EP300 inhibition blocks differentiation of TSCs into both EVT and STB lineages, and results in an expansion of TSC-like cells under differentiation-inducing conditions. Specific targeting by RNA interference or CRISPR/Cas9-mediated mutagenesis demonstrated that knockdown of EP300 but not CREBBP, inhibits trophoblast differentiation, consistent with the complications seen in Rubinstein–Taybi syndrome pregnancies. By transcriptome sequencing, we identified transforming growth factor alpha (TGFA, encoding TGF-α) as being strongly upregulated upon EP300 knockdown. Moreover, supplementing differentiation medium with TGF-α, which is a ligand for the epidermal growth factor receptor (EGFR), likewise affected trophoblast differentiation and resulted in increased TSC-like cell proliferation. These findings suggest that EP300 facilitates trophoblast differentiation by interfering with at least EGFR signaling, pointing towards a crucial role for EP300 in early human placentation.

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RNA-seq analysis of EP300 and CREBBP knockdown in human trophoblast stem cells and extravillous trophoblasts

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