MSX2 safeguards syncytiotrophoblast fate of human TSCs
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ABSTRACT:
PROVIDER: PRJNA698792 | ENA |
REPOSITORIES: ENA
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Project description:The majority of placental pathologies arise from failures in trophoblast differentiation, yet the underlying transcriptional regulation is poorly understood. Here, we use human trophoblast stem cells to elucidate the function of the transcription factor MSX2 in trophoblast specification. We show that depletion of MSX2 de-represses the syncytiotrophoblast program, while forced expression of MSX2 blocks it. We demonstrate that a large proportion of the affected genes are directly bound and regulated by MSX2 and identify components of the SWI/SNF complex as its strong interactors. Our findings uncover the pivotal role of MSX2 in cell fate decisions that govern human placental development and function.
2021-08-28 | GSE165970 | GEO
Project description:The placenta is an organ with extraordinary phenotypic diversity in eutherian mammals. Recent evidence suggest that numerous human placental enhancers are evolved from lineage-specific insertions of endogenous retroviruses (ERVs), yet the transcription factors (TFs) underlying their regulation remain largely elusive. Here, by first focusing on MER41, a primate-specific ERV family previously linked to placenta and innate immunity, we uncover the binding motifs of multiple crucial trophoblast TFs (GATA2/3, MSX2, GRHL2) in addition to innate immuninty TFs STAT1 and IRF1. Integration of ChIP-Seq data confirms the binding of GATA2/3 and MSX2 on the majority of MER41-derived enhancers in human trophoblast stem cells (TSCs). Notably, the usb-family composition of MER41-derived enhancers that are active in human TSCs are distinct from those activated upon interferon stimulation, which is determined by the binding of trophoblast TFs. We further demonstrate that GATA2/3 and MSX2 have prevalent binding on numerous other ERV families – indicating their broad impact on ERV-derived placental enhancers. Functionally, the derepression of many syncytiotrophoblast genes after disruption of MSX2 is likely to be mediated by enhancers derived from ERVs – suggesting ERVs are also important for mediating transcriptional repression in human TSCs. Overall, this study characterized the prevalent binding of GATA2/3, MSX2 and their co-factors on ERV-derived enhancers in human TSCs and provided mechanistic insights into the importance of ERVs in human trophoblast regulatory network.
2023-01-01 | GSE209536 | GEO
Project description:The placenta is an organ with extraordinary phenotypic diversity in eutherian mammals. Recent evidence suggest that numerous human placental enhancers are evolved from lineage-specific insertions of endogenous retroviruses (ERVs), yet the transcription factors (TFs) underlying their regulation remain largely elusive. Here, by first focusing on MER41, a primate-specific ERV family previously linked to placenta and innate immunity, we uncover the binding motifs of multiple crucial trophoblast TFs (GATA2/3, MSX2, GRHL2) in addition to innate immuninty TFs STAT1 and IRF1. Integration of ChIP-Seq data confirms the binding of GATA2/3 and MSX2 on the majority of MER41-derived enhancers in human trophoblast stem cells (TSCs). Notably, the usb-family composition of MER41-derived enhancers that are active in human TSCs are distinct from those activated upon interferon stimulation, which is determined by the binding of trophoblast TFs. We further demonstrate that GATA2/3 and MSX2 have prevalent binding on numerous other ERV families – indicating their broad impact on ERV-derived placental enhancers. Functionally, the derepression of many syncytiotrophoblast genes after disruption of MSX2 is likely to be mediated by enhancers derived from ERVs – suggesting ERVs are also important for mediating transcriptional repression in human TSCs. Overall, this study characterized the prevalent binding of GATA2/3, MSX2 and their co-factors on ERV-derived enhancers in human TSCs and provided mechanistic insights into the importance of ERVs in human trophoblast regulatory network.
2023-01-01 | GSE209540 | GEO
Project description:The commitment and differentiation of human placental progenitor cytotrophoblast (CT) cells are crucial for a successful pregnancy, but the underlying regulatory mechanism remains poorly understood. Here we identified the transcription factor (TF), Specificity protein 6 (SP6), as a human species-specific trophoblast lineage TF expressed in human placental CT cells. Using pluripotent stem cells as a model, we demonstrated that SP6 governs CT generation and the establishment of trophoblast stem cells (TSCs) and discovered msh homeobox 2 (MSX2) as the downstream effector in these events. Mechanistically, we showed that SP6 interacts with histone acetyltransferase P300 to modulate the landscape of H3K27ac at targeted regulatory elements, thereby favoring transcriptional activation and facilitating CT cell fate decisions and TSC maintenance. Our results established SP6 as a novel regulator of the human trophoblast lineage and implied its regulatory role in placental development and the pathogenies of placental diseases.
2024-03-11 | GSE236795 | GEO
Project description:The commitment and differentiation of human placental progenitor cytotrophoblast (CT) cells are crucial for a successful pregnancy, but the underlying regulatory mechanism remains poorly understood. Here we identified the transcription factor (TF), Specificity protein 6 (SP6), as a human species-specific trophoblast lineage TF expressed in human placental CT cells. Using pluripotent stem cells as a model, we demonstrated that SP6 governs CT generation and the establishment of trophoblast stem cells (TSCs) and discovered msh homeobox 2 (MSX2) as the downstream effector in these events. Mechanistically, we showed that SP6 interacts with histone acetyltransferase P300 to modulate the landscape of H3K27ac at targeted regulatory elements, thereby favoring transcriptional activation and facilitating CT cell fate decisions and TSC maintenance. Our results established SP6 as a novel regulator of the human trophoblast lineage and implied its regulatory role in placental development and the pathogenies of placental diseases.
2024-03-11 | GSE236794 | GEO
Project description:Stem cells reside in specific niches providing stemness-maintaining environments. Thus, the regulated migration from these niches is associated with differentiation onset. However, mechanisms retaining stem cells in their niche remain poorly understood. Here, we show that the epigenetic regulator lysine-specific demethylase 1 (Lsd1) organises the trophoblast niche of the early mouse embryo by coordinating migration and invasion of trophoblast stem cells (TSCs). Lsd1 deficiency leads to the depletion of the stem cell pool resulting from precocious migration of TSCs. Migration is induced by premature expression of the transcription factor Ovol2 that is repressed by Lsd1 in undifferentiated wild-type TSCs. Increasing Ovol2 levels suffices to recapitulate the migration phenotype. Furthermore, Lsd1-deficient TSCs exhibit a developmental bias towards cells of the syncytiotrophoblast and impaired spongiotrophoblast and trophoblast giant cell differentiation. In summary, we describe that the epigenetic modifier Lsd1 coordinates placental development by retaining TSCs in their niche and directing trophoblast differentiation. Mouse trophoblast stem cells (TSCs) were isoloated from a single conditional Lsd1-deficient mouse (Lsd1tm1SchM-CM-<le). Deletion of Lsd1 was induced eight days before the collection of RNA by addition of 0.2 M-BM-5M 4OH-tamoxife. Cells were isolated at successive stages of differentiation for total RNA extraction and hybridization on Affymetrix microarrays. To that end, we harvested cells at three time-points: before induction of differentiation (d0), two days after induction of differentiation (d2), and four days after induction of differentiation (d4). Three replicates (1, 2, 3) for control (-) and Lsd1-deficeint (+) cells were included for each differentiation stage.
2014-01-17 | E-GEOD-38277 | biostudies-arrayexpress
Project description:The concept of tumor stem cells (TSCs) provides a new paradigm for understanding tumor biology, although it remains unclear whether TSCs will prove to be a more robust model than traditional cancer cell lines. We demonstrate marked phenotypic and genotypic differences between primary human tumor-derived TSCs and their matched glioma cell lines. TSCs derived directly from primary glioblastomas harbor extensive similarities to normal NSC and recapitulate the genotype, gene expression patterns and in vivo biology of human glioblastomas. By contrast, the matched, traditionally grown tumor cell lines do not secondary to in vitro genomic alterations. These findings suggest that TSCs may be a more reliable model than many commonly utilized cancer cell lines for understanding the biology of primary human tumors. Analysis of gene expression data is described in Lee et al., Cancer Cell, 2006. Experiment Overall Design: To further understand the differences between NBE- and serum-cultured GBM cells, we generated gene expression profiles of NBE-cells, serum-cells, their derived xenograft tumors, and the original GBMs taken directly from the patients. NBE- and serum-cultured GBM cells from different passages were also included in the analyses in order to evaluate the potential effects of in vitro passage number on gene expression.
2008-06-13 | E-GEOD-4536 | biostudies-arrayexpress
Project description:Trophoblast stem cells (TSCs) are derived from the trophoectoderm of a blastocyst and can maintain self-renewal in vitro. Meanwhile, essential insights into the molecular mechanisms controlling placental developmental could be gained by using TSCs that can differentiate into the various placental trophoblast cell types in vitro. Esrrb is a transcription factor with pivotal roles in maintaining TSCs’ self-renewal, but the exact transcriptional networks that Esrrb involved in TSCs are largely unknown. In the present study, we elucidated the function of Esrrb during TSC self-renewal and differentiation. We demonstrate that precise levels of Essrb are critical for TSCs stemness maintenance and normal trophoblast differentiation, as Esrrb depletion results in down-regulation of the key TSC-specific transcription factors, consequently causing TSCs differentiation and forced expression of Esrrb can partially block TSCs differentiation in the absence of FGF4. This function of Esrrb is exerted by directly binding and activating a core set of TSC-specific target genes including Cdx2, Eomes, Sox2, Fgfr4 and BMP4. Furthermore, we investigate the role of Esrrb in reprogramming of mouse embryonic fibroblasts (MEFs) to induced TSCs (iTSCs). We show that Esrrb can facilitate the conversion of iTSCs from MEFs. Moreover, Esrrb can substitute for Eomes during this conversion process. Our findings provide a better understanding of the molecular mechanism of Esrrb in maintaining TSCs self-renewal and iTSCs reprogramming.
2019-10-06 | GSE104695 | GEO
Project description:Trophoblast stem cells (TSCs) are derived from the trophoectoderm of a blastocyst and can maintain self-renewal in vitro. Meanwhile, essential insights into the molecular mechanisms controlling placental developmental could be gained by using TSCs that can differentiate into the various placental trophoblast cell types in vitro. Esrrb is a transcription factor with pivotal roles in maintaining TSCs’ self-renewal, but the exact transcriptional networks that Esrrb involved in TSCs are largely unknown. In the present study, we elucidated the function of Esrrb during TSC self-renewal and differentiation. We demonstrate that precise levels of Essrb are critical for TSCs stemness maintenance and normal trophoblast differentiation, as Esrrb depletion results in down-regulation of the key TSC-specific transcription factors, consequently causing TSCs differentiation and forced expression of Esrrb can partially block TSCs differentiation in the absence of FGF4. This function of Esrrb is exerted by directly binding and activating a core set of TSC-specific target genes including Cdx2, Eomes, Sox2, Fgfr4 and BMP4. Furthermore, we investigate the role of Esrrb in reprogramming of mouse embryonic fibroblasts (MEFs) to induced TSCs (iTSCs). We show that Esrrb can facilitate the conversion of iTSCs from MEFs. Moreover, Esrrb can substitute for Eomes during this conversion process. Our findings provide a better understanding of the molecular mechanism of Esrrb in maintaining TSCs self-renewal and iTSCs reprogramming.
2019-10-06 | GSE104694 | GEO
Project description:We performed scRNA seq according to the CEL-seq2 protocol in order to define the equivalent developmental stages of TSCs
2019-03-06 | GSE127754 | GEO