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ESRRB Facilitates the Conversion of Trophoblast-Like Stem Cells From Induced Pluripotent Stem Cells by Directly Regulating CDX2.

ABSTRACT: Porcine-induced pluripotent stem cells (piPSCs) could serve as a great model system for human stem cell preclinical research. However, the pluripotency gene network of piPSCs, especially the function for the core transcription factor estrogen-related receptor beta (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. Our results demonstrated a unique and crucial role of ESRRB in determining piPSCs fate, and shed new light on the molecular mechanism underlying the segregation of embryonic and extra-embryonic lineages.

SUBMITTER: Yu S

PROVIDER: S-EPMC8488167 | biostudies-literature |

REPOSITORIES: biostudies-literature

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ESRRB Facilitates the Conversion of Trophoblast-like Stem Cells from Induced Pluripotent Stem cells by Directly Regulating KRT8 and CDX2

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

ESRRB facilitates the conversion of Trophoblast-like Stem Cells from induced pluripotent stem cells by directly regulating KRT8 and CDX2

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-10-14 | GSE180058 | GEO

ESRRB facilitates the conversion of Trophoblast-like Stem Cells from induced pluripotent stem cells by directly regulating KRT8 and CDX2 [RNA-seq]

Project description:Studies on porcine induced pluripotent stem cells (piPSCs) served as a great reference for human clinical research. However, the pluripotency genes network of piPSCs, especially the core transcription factor ESRRB, was currently poor understand. Here, we constructed an overexpressing ESRRB piPSC line (ESRRB piPSCs) in which ESRRB expression was efficiently enhanced. It was found that ESRRB piPSCs showed scattered and flat colonies, moreover, the ESRRB piPSCs showed higher chimeric capacity into trophectoderm than that of CON piPSCs. We also found that ESRRB could directly regulate the expressions of the trophoblast stem cells (TSCs) markers, such as KRT8, KRT18 and CDX2, through binding in their promoter regions. Functional analysis of the mutant domains of ESRRB proved. that the zinc finger domain was indispensable for ESRRB to regulate TSCs markers. Moreover, the regulated process needed the participation of OCT4. Accordingly, ESRRB cooperating with OCT4 promoted TSCs markers to facilitate the conversion from the pluripotent state to trophoblastic-like state. Our results revealed the unique and crucial role of ESRRB in the determination of piPSCs fate and provided opportunities for studying the barriers underlying embryonic and extra-embryonic lineage segregation.

2021-10-14 | GSE180057 | GEO

ESRRB facilitates the conversion of Trophoblast-like Stem Cells from induced pluripotent stem cells by directly regulating KRT8 and CDX2 [ChIP-seq]

2021-10-14 | GSE180056 | GEO

KDM4C Contributes to Trophoblast-like Stem Cell Conversion from Porcine-Induced Pluripotent Stem Cells (piPSCs) via Regulating CDX2.

Project description:Studies on ESRRB-regulating porcine-induced pluripotent stem cells (piPSCs) converted to trophoblast-like stem cells (TLSCs) contribute to the understanding of early embryo development. However, the epigenetic modification regulation network during the conversion is poorly understood. Here, the global change in histone H3 Lysine 4, 9, 27, 36 methylation and Lysine 27 acetylation was investigated in piPSCs and TLSCs. We found a high modification profile of H3K36me2 in TLSCs compared to that of piPSCs, whereas the profiles of other modifications remained constant. KDM4C, a H3K36me3/2 demethylase, whose gene body region was combined with ESRRB, was upregulated in TLSCs. Moreover, KDM4 inhibitor supplementation rescued the AP-negative phenotype observed in TLSCs, confirming that KDM4C could regulate the pluripotency of TLSCs. Subsequently, KDM4C replenishment results show the significantly repressed proliferation and AP-positive staining of TLSCs. The expressions of CDX2 and KRT8 were also upregulated after KDM4C overexpression. In summary, these results show that KDM4C replaced the function of ESRRB. These findings reveal the unique and crucial role of KDM4C-mediated epigenetic chromatin modifications in determination of piPSCs' fate and expand the understanding of the connection between piPSCs and TSCs.

| S-EPMC9323581 | biostudies-literature

ESRRB facilitates the conversion of Trophoblast-like Stem Cells from induced pluripotent stem cells by directly regulating KRT8 and CDX2

Project description:ESRRB facilitates the conversion of Trophoblast-like Stem Cells from induced pluripotent stem cells by directly regulating KRT8 and CDX2

| PRJNA746345 | ENA

ESRRB facilitates the conversion of Trophoblast-like Stem Cells from induced pluripotent stem cells by directly regulating KRT8 and CDX2 [RNA-seq]

Project description:ESRRB facilitates the conversion of Trophoblast-like Stem Cells from induced pluripotent stem cells by directly regulating KRT8 and CDX2 [RNA-seq]

| PRJNA746347 | ENA

ESRRB facilitates the conversion of Trophoblast-like Stem Cells from induced pluripotent stem cells by directly regulating KRT8 and CDX2 [ChIP-seq]

Project description:ESRRB facilitates the conversion of Trophoblast-like Stem Cells from induced pluripotent stem cells by directly regulating KRT8 and CDX2 [ChIP-seq]

| PRJNA746346 | ENA

Cdx2 efficiently induces trophoblast stem-like cells in naive, but not primed, pluripotent stem cells.

Project description:Diverse pluripotent stem cell lines have been derived from the mouse, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), embryonal carcinoma cells (ECCs), and epiblast stem cells (EpiSCs). While all are pluripotent, these cell lines differ in terms of developmental origins, morphology, gene expression, and signaling, indicating that multiple pluripotent states exist. Whether and how the pluripotent state influences the cell line's developmental potential or the competence to respond to differentiation cues could help optimize directed differentiation protocols. To determine whether pluripotent stem cell lines differ in developmental potential, we compared the capacity of mouse ESCs, iPSCs, ECCs, and EpiSCs to form trophoblast. ESCs do not readily differentiate into trophoblast, but overexpression of the trophoblast-expressed transcription factor, CDX2, leads to efficient differentiation to trophoblast and to formation of trophoblast stem cells (TSCs) in the presence of fibroblast growth factor-4 (FGF4) and Heparin. Interestingly, we found that iPSCs and ECCs could both give rise to TSC-like cells following Cdx2 overexpression, suggesting that these cell lines are equivalent in developmental potential. By contrast, EpiSCs did not give rise to TSCs following Cdx2 overexpression, indicating that EpiSCs are no longer competent to respond to CDX2 by differentiating to trophoblast. In addition, we noted that culturing ESCs in conditions that promote naïve pluripotency improved the efficiency with which TSC-like cells could be derived. This work demonstrates that CDX2 efficiently induces trophoblast in more naïve than in primed pluripotent stem cells and that the pluripotent state can influence the developmental potential of stem cell lines.

| S-EPMC4440987 | biostudies-literature

Lineage conversion of murine extraembryonic trophoblast stem cells to pluripotent stem cells.

Project description:In mammals, the first cell fate decision is initialized by cell polarization at the 8- to 16-cell stage of the preimplantation embryo. At this stage, outside cells adopt a trophectoderm (TE) fate, whereas the inside cell population gives rise to the inner cell mass (ICM). Prior to implantation, transcriptional interaction networks and epigenetic modifications divide the extraembryonic and embryonic fate irrevocably. Here, we report that extraembryonic trophoblast stem cell (TSC) lines are converted to induced pluripotent stem cells (TSC-iPSCs) by overexpressing Oct4, Sox2, Klf4, and cMyc. Methylation studies and gene array analyses indicated that TSC-iPSCs had adopted a pluripotent potential. The rate of conversion was lower than those of somatic reprogramming experiments, probably due to the unique genetic network controlling extraembryonic lineage fixation. Both in vitro and in vivo, TSC-iPSCs differentiated into tissues representing all three embryonic germ layers, indicating that somatic cell fate could be induced. Finally, TSC-iPSCs chimerized the embryo proper and contributed to the germ line of mice, indicating that these cells had acquired full somatic differentiation potential. These results lead to a better understanding of the molecular processes that govern the first lineage decision in mammals.

| S-EPMC3126346 | biostudies-literature

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