Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of Trophoblast Stem Cells
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Project description:Esrrb is a transcription factor implicated in embryonic stem (ES) cell self-renewal, yet its knockout causes intrauterine lethality due to defects in trophoblast development. Here we show that in trophoblast stem (TS) cells, Esrrb is a downstream target of fibroblast growth factor (Fgf) signalling and is critical to drive TS cell self-renewal. In contrast to its occupancy of pluripotency-associated loci in ES cells, Esrrb sustains the stemness of TS cells by direct binding and regulation of TS cell-specific transcription factors including Elf5 and Eomes. To elucidate the mechanisms whereby Esrrb controls the expression of its targets, we characterized its TS cell-specific interactome by mass spectrometry. Unlike in ES cells, Esrrb interacts in TS cells with the histone demethylase Lsd1 and with the RNA Polymerase II-associated Integrator complex. Our findings provide new insights into both, the general and context-dependent wiring of transcription factor networks in stem cells by master transcription factors.
2015-07-24 | PXD002183 | Pride
Project description:Derivation and maintenance of TS cells depends on the presence of Fgf signalling. Numerous gene knock-out experiments identified the mitogen activated kinase Mek/Erk branch of the Fgf signalling pathway as predominantly active in both TS cells and extraembryonic ectoderm. Therefore, we tested changes in expression of the key TS cell transcription factors (TFs) upon Mek/Erk inhibition using the Mek inhibitor PD0325901 (“PD03”). To obtain an unbiased genome-wide coverage of the immediate-early response genes of Mek inhibition in TS cells, we performed RNA-seq analysis after 3h and 24h of PD03 treatment. Notably, of the known TS cell TFs, this analysis confirmed Esrrb as the earliest, most rapidly silenced gene upon PD03 treatment. In order to gain first insights into which genes may be primary targets of Esrrb, we treated TS cells with the synthetic nonsteroidal estrogen diethylstilbestrol (DES), an estrogen-related receptor (Err) antagonist and also performed RNA-seq upon short (24h) and prolonged (4d) DES treatment. Finally, to obtain a comprehensive global overview of the binding sites of Esrrb in TS cells, and of its interaction with Lsd1 and Nr0b1 (Dax1), we performed chromatin immunoprecipitation (ChIP)-seq experiments on these factors.
2015-08-18 | E-MTAB-3565 | biostudies-arrayexpress
Project description: Not available
| S-EPMC4525203 | biostudies-literature
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:Here, we demonstrate that upon inhibition of the Fgf/Erk pathway in mouse trophoblast stem cells (TSCs), the Ets2 repressor factor (Erf) interacts with components of the Nuclear Receptor Corepressor Complex 1 and 2 (NCoR1 and NCoR2). Upon attenuation of Fgf signalling, unphosphorylated, nuclear Erf recruits the NCoR1/2 complex to key trophoblast genes, brings about their transcriptional silencing and facilitates differentiation and placental development.
2023-04-26 | PXD037892 | Pride
Project description:Porcine induced pluripotent stem cells (piPSCs) could serve as a great model system for human stem cell pre-clinical research. However, the pluripotency gene network of piPSCs, especially the function for the core transcription factor ESRRB, was poorly understood. Here, we constructed ESRRB-overexpressing piPSCs (ESRRB-piPSCs). Compared with the control piPSCs (CON-piPSCs), the ESRRB-piPSCs showed flat, monolayered colony morphology. Moreover, the ESRRB-piPSCs showed greater chimeric capacity into trophectoderm than CON-piPSCs. We found that ESRRB could directly regulate the expressions of trophoblast stem cell (TSC)-specific markers, including KRT8, KRT18 and CDX2, through binding to their promoter regions. Mutational analysis proved that the N-terminus zinc finger domain is indispensable for ESRRB to regulate the TSC markers. Furthermore, this regulation needs the participation of OCT4. Accordingly, the cooperation between ESRRB and OCT4 facilitates the conversion from pluripotent state to the trophoblast-like state.
2022-02-17 | PXD027539 | Pride
Project description:To understand the mechanism underlying the versatility in transcriptional regulation by Sox2 and Esrrb, we compared genome-wide binding sites of Sox2 and Esrrb in embryonic stem (ES) cells and trophoblast stem (TS) cells by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq).
2013-10-17 | GSE28453 | GEO
Project description:Placental development relies on coordinated cell fate decisions governed by signalling inputs. However, little is known about how signalling cues are transformed into repressive lineage-specific transcriptional signatures. Here, we demonstrate that upon inhibition of the Fgf/Erk pathway in mouse trophoblast stem cells (TSCs), the Ets2 repressor factor (Erf) interacts with the Nuclear Receptor Corepressor Complex 1 and 2 (NCoR1/2) and recruits it to key trophoblast genes. Genetic ablation of Erf or Tbl1x (a component of the NCoR1/2 complex) abrogates the Erf/NCoR1/2 interaction. This leads to mis-expression of Erf/NCor1/2 target genes resulting in a TSC differentiation defect. Mechanistically, Erf regulates expression of these genes by recruiting the NCoR1/2 complex to their enhancers and modulation of H3K27ac. Our findings uncover how the Fgf/Erf/NCoR1/2 repressive axis governs cell fate and placental development, providing a new paradigm for Fgf-mediated transcriptional control.
2023-04-26 | GSE199024 | GEO
Project description:Estrogen related receptor beta (Esrrb) is an orphan nuclear receptor that is required for self-renewal and pluripotency in mouse embryonic stem (ES) cells. However, in the early post-implantation mouse embryo, Esrrb is specifically expressed in the extraembryonic ectoderm (ExE) and plays a crucial role in trophoblast development. In this study, to better understand the function of Esrrb in trophoblast lineage cells, we performed microarray analysis of Esrrb-null mutant versus wild-type mouse embryos. To further characterize the regulatory targets of Esrrb, we treated trophoblast stem (TS) cells with either Esrrb inhibitor DES or vehicle and compared their global gene expression profile via RNA-seq analysis. In addition, to ask whether these target genes are directly regulated by Esrrb, we performed Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis of TS cells using anti-Esrrb antibody.
2019-07-15 | GSE123360 | GEO