Gene expression profiling reveals a novel regulatory role for Sox21 in mouse trophoblast stem cell differentiation.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE67037 | GEO | 2015/11/10
SECONDARY ACCESSION(S): PRJNA278763
REPOSITORIES: GEO
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Project description:In this study we introduced Sox21 as a new regulator of trophoblast stem cell (TSC) differentiation. The transcriptome of different cell types were analyzed and compared to identify a TSC gene signature. In order to identify novel TSC specific genes, we performed genome-wide expression profiling of TSCs, embryonic stem cells, epiblast stem cells, and mouse embryo fibroblasts derived from mice of the same genetic background (129S1/SvImJ).
2015-11-10 | E-GEOD-67037 | biostudies-arrayexpress
Project description:Appropriate self-renewal and differentiation of trophoblast stem cells (TSCs) are key factors for proper placental development and function and, in turn, for appropriate in utero fetal growth. To identify novel TSC-specific genes, we performed genome-wide expression profiling of TSCs, embryonic stem cells, epiblast stem cells, and mouse embryo fibroblasts, derived from mice of the same genetic background. Our analysis revealed a high expression of Sox21 in TSCs compared with other cell types. Sox21 levels were high in undifferentiated TSCs and were dramatically reduced upon differentiation. In addition, modulation of Sox21 expression in TSCs affected lineage-specific differentiation, based on both marker analysis and functional assessment. Our results implicate Sox21 specifically in the promotion of spongiotrophoblast and giant cell differentiation and establish a new mechanism through which trophoblast sublineages are specified.
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Project description:Elf5 is a transcription factor with pivotal roles in the trophoblast compartment where it reinforces a trophoblast stem cell (TSC)-specific transcriptional circuit. However, Elf5 is also present in differentiating trophoblast cells that have ceased to express other TSC genes such as Cdx2 and Eomes. In the current study we aimed to elucidate the context-dependent role of Elf5 at the interface between TSC self-renewal and onset of differentiation. We demonstrate that precise levels of Elf5 are critical for normal expansion of the TSC compartment and embryonic survival, as Elf5 overexpression triggers precocious trophoblast differentiation. Through integration of protein interactome, transcriptome and genome-wide chromatin immunoprecipitation data we reveal that this abundance-dependent function is mediated through a shift in preferred Elf5 binding partners; in TSCs, Elf5 interaction with Eomes recruits Tfap2c to triply occupied sites at TSC-specific genes driving their expression. By contrast, the Elf5 and Tfap2c interaction becomes predominant as their protein levels increase. This triggers binding to double and single occupancy sites that harbour the cognate Tfap2c motif, causing activation of the associated differentiation-promoting genes. These data place Elf5 at the centre of a stoichiometry-sensitive transcriptional network where it acts as molecular switch governing the balance between TSC proliferation and differentiation.
2015-12-01 | PXD003145 | Pride
Project description:This study aims to compare in vivo human trophoblast differentiation into EVTs to different in vitro trophoblast organoids using single-cell and single-nuclei RNA sequencing. The study includes two type of systems: human primary trophoblast organoids (PTO) and trophoblast stem cells (TSCs). Trophoblast stem cell (TSC) lines BTS5 and BTS11 derived by Okae and colleagues were grown as described previously (Okae et al. 2018) and together with EVT media. Primary trophoblast organoids (PTO) were grown and differentiated into EVT as previously described by Turco & Sheridan (Turco et al 2018; Sheridan et al 2020). This study shows that the main regulatory programs mediating EVT invasion in vivo are preserved in in vitro models of EVT differentiation from primary trophoblast organoids and trophoblast stem cells.
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Project description:Cells belonging to trophoblast lineage are required for proper implantation and placentation, as well as the vascular, hematopoietic, and immunological properties of the placenta, a crucial organ mediating dynamic interactions between maternal and fetal tissues. Defects in trophoblast lineage development can cause early pregnancy failure or other pregnancy-related disorders. Despite its pivotal roles, the placenta remains as one of the least studied organs. Until now, only a handful of trophoblast-specific transcription factors (TFs) have been characterized, and underlying regulatory mechanisms modulating trophoblast lineage development remain poorly understood. Here we explore trophoblast stem cell (TSC)-specific super-enhancers (SEs) and subsequently identify SE-associated factors enriched with previously known and many unknown TFs modulating trophoblast lineage development. By mapping direct targets of 28 TSC-specific TFs in TSCs, we construct highly intertwined transcriptional regulatory networks where TFs are co-regulated and linked with signaling pathways, and which function as cellular modules dedicated to trophoblast lineage development. Additionally, we reveal that TSC-specific TFs alter their target sites corresponding to the reshaped enhancers during TSC differentiation. These findings advance our understanding on placenta biology.
2019-09-25 | GSE110950 | GEO
Project description:In this study we identified that Sirt1 is important for mouse trophoblast stem cell (TSC) differentiation. The transcriptome of wild-type and Sirt1-null TSC were analyzed to identify dysregulation of signaling pathways.
2018-01-24 | GSE100279 | GEO
Project description:We derive experimental conditions for the derivation of marmoset trophoblast like cells. Marmoset naïve PSC form extraembryonic mesoderm in human TSC conditions, whilst TGFβ/NODAL, FGF/ERK and WNT signalling control marmoset peri- and postimplantation trophoblast identity.
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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.
2023-12-19 | GSE250424 | GEO
Project description:Generation of brain region-specific progenitors from human embryonic stem cells (hESCs) is critical for their application. However, transcriptional regulation of neural regionalization in human embryos is poorly understood. Here, we report that transcription factor SOX21 is required for telencephalic fate specification from hESCs. SOX21 knockout (KO) impairs telencephalic fate specification, concomitant with the activation of diencephalic genes and Wnt signaling. Inhibition of Wnt signaling restores telencephalic specification from SOX21 KO hESCs. Analysis of global SOX21 DNA binding profiles and SOX21-regulated genes identifies SOX21 targets. SOX21 interacts with b-catenin and interferes with TCF4/b-catenin binding to the enhancer of WNT8B. Double KO of SOX21 and WNT8B restores telencephalic specification, indicating that SOX21 specifies the telencephalic fate through repressing WNT8B expression. Moreover, the high and low levels of SOX21 in the telencephalon and diencephalon, respectively, in developing human brains support its role in telencephalic fate specification. Collectively, this study unveils previously unappreciated roles of SOX21 and sheds light on the transcriptional control of telencephalic patterning in humans.
2019-10-28 | GSE138094 | GEO
Project description:Generation of brain region-specific progenitors from human embryonic stem cells (hESCs) is critical for their application. However, transcriptional regulation of neural regionalization in human embryos is poorly understood. Here, we report that transcription factor SOX21 is required for telencephalic fate specification from hESCs. SOX21 knockout (KO) impairs telencephalic fate specification, concomitant with the activation of diencephalic genes and Wnt signaling. Inhibition of Wnt signaling restores telencephalic specification from SOX21 KO hESCs. Analysis of global SOX21 DNA binding profiles and SOX21-regulated genes identifies SOX21 targets. SOX21 interacts with b-catenin and interferes with TCF4/b-catenin binding to the enhancer of WNT8B. Double KO of SOX21 and WNT8B restores telencephalic specification, indicating that SOX21 specifies the telencephalic fate through repressing WNT8B expression. Moreover, the high and low levels of SOX21 in the telencephalon and diencephalon, respectively, in developing human brains support its role in telencephalic fate specification. Collectively, this study unveils previously unappreciated roles of SOX21 and sheds light on the transcriptional control of telencephalic patterning in humans.
2019-10-28 | GSE110504 | GEO