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Fosl1 transdifferentiate embryonic stem cells to differentiated trophoblast stem cells (RNA-seq)

ABSTRACT: During mammalian embryonic development, the first lineage commitment event gives rise to two distinct cell populations: the trophectoderm (TE) and the inner cell mass (ICM). The TE consists of outer cells of the blastocyst and ultimately forms the placenta while the ICM gives rise to all the embryonic tissues. Numerous transcription factors (TFs) guiding ICM differentiation into different embryonic tissues have been characterized. However, only a few TFs that are required for TE specification and differentiation have been identified, and much less is understood as to how these TFs interact with other TFs or with their chromosomal targets in order to drive cell fate towards TE lineage. Understanding trophectoderm development is crucial because cells in this lineage are required for proper embryo implantation in the uterus. Defects in this lineage can cause early failure of pregnancy as well as other pregnancy related disorders such as preeclampsia and intrauterine growth restriction (IUGR). Here, we characterize the function of one of TE-specific TF, Fosl1, which was previously suggested as having some role in placental development. We utilized mouse embryonic stem (ES) cells (derived from ICM) and showed that ectopic expression of Fosl1 can transdifferentiate ES cells to differentiated TS cells (trophoblast giant-like cells). We show that Fosl1 does so by directly binding and activating TE specific genes and genes associated with epithelial-mesenchymal transition (EMT). Using mouse trophoblast stem (TS) cells, we also establish that Fosl1 is required for specification of TS cells to trophoblast giant cells (TGCs) subtype. Therefore, we postulate that Fosl1 is a key regulator of TS cell differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE99984 | GEO | 2018/04/25

REPOSITORIES: GEO

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Fosl1 transdifferentiate embryonic stem cells to differentiated trophoblast stem cells. (ChIP-seq)

Project description:During mammalian embryonic development, the first lineage commitment event gives rise to two distinct cell populations: the trophectoderm (TE) and the inner cell mass (ICM). The TE consists of outer cells of the blastocyst and ultimately forms the placenta while the ICM gives rise to all the embryonic tissues. Numerous transcription factors (TFs) guiding ICM differentiation into different embryonic tissues have been characterized. However, only a few TFs that are required for TE specification and differentiation have been identified, and much less is understood as to how these TFs interact with other TFs or with their chromosomal targets in order to drive cell fate towards TE lineage. Understanding trophectoderm development is crucial because cells in this lineage are required for proper embryo implantation in the uterus. Defects in this lineage can cause early failure of pregnancy as well as other pregnancy related disorders such as preeclampsia and intrauterine growth restriction (IUGR). Here, we characterize the function of one of TE-specific TF, Fosl1, which was previously suggested as having some role in placental development. We utilized mouse embryonic stem (ES) cells (derived from ICM) and showed that ectopic expression of Fosl1 can transdifferentiate ES cells to differentiated TS cells (trophoblast giant-like cells). We show that Fosl1 does so by directly binding and activating TE specific genes and genes associated with epithelial-mesenchymal transition (EMT). Using mouse trophoblast stem (TS) cells, we also establish that Fosl1 is required for specification of TS cells to trophoblast giant cells (TGCs) subtype. Therefore, we postulate that Fosl1 is a key regulator of TS cell differentiation.

2018-04-25 | GSE99983 | GEO

Establishment of trophoblast stem cells under defined culture conditions in mice

Project description:The inner cell mass (ICM) and trophoblast cell lineages duet early embryonic development in mammals. After implantation, the ICM forms the embryo proper as well as some extraembryonic tissues, whereas the trophoectoderm (TE) exclusively forms the fetal portion of the placenta and the trophoblast giant cells. Although embryonic stem (ES) cells can be derived from ICM in cultures of mouse blastocysts in the presence of LIF and/or combinations of small-molecule chemical compounds, and the undifferentiated pluripotent state can be stably maintained without use of serum and feeder cells, defined culture conditions for derivation and maintenance of undifferentiated trophoblast stem (TS) cells have not been established. Here, we report that addition of FGF2, activin A, XAV939, and Y27632 are necessary and sufficient for derivation of TS cells from both of E3.5 blastocysts and E6.5 early postimplantation extraembryonic ectoderm. Moreover, the undifferentiated TS cell state can be stably maintained in chemically defined culture conditions. Cells derived in this manner expressed TS cell marker genes, including Eomes, Elf5, Cdx2, Klf5, Cdh1, Esrrb, Sox2, and Tcfap2c; differentiated into all trophoblast subtypes (trophoblast giant cells, spongiotrophoblast, and labyrinthine trophoblast) in vitro; and exclusively contributed to trophoblast lineages in chimeric animals. This delineation of minimal requirements for derivation and self-renewal provides a defined platform for precise description and dissection of the molecular state of TS cells.

2014-07-08 | GSE59107 | GEO

Establishment of trophoblast stem cells under defined culture conditions in mice

2014-07-08 | E-GEOD-59107 | biostudies-arrayexpress

Lineage regulators TFAP2C and NR5A2 function as bipotency activators in totipotent embryos

Project description:During the first lineage segregation, a mammalian totipotent embryo differentiates into inner cell mass (ICM) and trophectoderm (TE). However, how transcription factors (TFs) regulate this earliest cell fate decision in vivo remains elusive, with their regulomes primarily inferred from cultured cells. Here, we investigated the TF regulomes during the first mouse lineage specification across 6 stages, spanning the pre-initiation, initiation, commitment, and maintenance phases. Unexpectedly, we found TFAP2C, a trophoblast regulator, bound and activated both early TE and ICM genes at the totipotent (2-8-cell) stages (“bipotency activation”). Tfap2c deficiency caused downregulation of early ICM genes, including Nanog, Nr5a2, Tdgf1, and early TE genes, including Tfeb and Itgb5 in 8-cell embryos. Transcription defects in both ICM and TE lineages were also found in blastocysts, accompanied by increased apoptosis and reduced cell numbers in ICMs. Upon trophoblast commitment, TFAP2C left early-ICM genes but acquired binding to late-TE genes in blastocysts where it co-bound with CDX2, and later to extra-embryonic ectoderm (ExE) genes where it cooperatively co-occupied with the former ICM regulator SOX2. Finally, “bipotency activation” in totipotent embryos also applied to a pluripotency regulator NR5A2 which similarly bound and activated both ICM and TE lineage genes at the 8-cell stage. These data reveal a unique transcription circuity of totipotency underpinned by highly adaptable lineage regulators.

2023-11-23 | GSE216256 | GEO

Altered Subcellular Localization of Transcription Factor TEAD4 Regulates First Mammalian Cell Lineage Commitment

Project description:In the preimplantation mouse embryo TEAD4 is critical to establishing the trophectoderm (TE)-specific transcriptional program and segregating TE from the inner cell mass (ICM). However, TEAD4 is expressed both in the TE and the ICM. Thus, differential function of TEAD4 rather than expression itself regulates specification of the first two cell lineages. We used ChIP-seq to define genome-wide TEAD4 target genes and asked how transcription of TEAD4 target genes is specifically maintained in the TE. Our analyses revealed an evolutionarily conserved mechanism, in which lack of nuclear localization of TEAD4 impairs the TE-specific transcriptional program in inner blastomeres, thereby allowing their maturation towards the ICM lineage. Restoration of TEAD4 nuclear localization maintains the TE-specific transcriptional program in the inner blastomeres and prevents segregation of the TE and ICM lineages and blastocyst formation. We propose that altered subcellular localization of TEAD4 in blastomeres dictates first mammalian cell fate specification. ChIPseq profiles of TEAD4, IgG, Input in Mouse trophoblast stem cells using Illumina HiSeq 2000 and Illumina Genome Analyzer IIx

2012-04-18 | E-GEOD-37350 | biostudies-arrayexpress

Arid3a is required for mammalian placenta development

Project description:Previous studies in the mouse indicated that Arid3a plays a critical role in the first cell fate decision required for generation of trophectoderm (TE). Here, we demonstrate that Arid3a is widely expressed during mouse and human placentation and essential for early embryonic viability. Arid3a is located within trophoblast giant cells and other trophoblast-derived cell subtypes in the junctional and labyrinth zones of the placenta. Conventional Arid3a knockout embryos suffer restricted intrauterine growth with sever defects in placental structural organization. Arid3a null placentas show aberrant expression of subtype-specific markers as well as significant alteration in inflammatory response-related genes, cytokines and chemokines. We provide evidence that BMP4-mediated induction of trophoblast stem (TS)-like cells from human induced pluripotent (iPS) stem cells results in ARID3A upregulation and cytoplasmic to nuclear translocation. Overexpression of ARID3A in human iPS and BMP4-mediated TS-like cells up-regulated TE markers, whereas pluripotent markers were down-regulated. Our results indicate that the roles of Arid3a are conserved and essential for mammalian placental development through regulation of both intrinsic and extrinsic developmental programs. Placentas of E10.5 and E11.5 wild type (WT) and Arid3a-/- mice were generated by deep sequencing, using Illumina

2016-07-01 | E-GEOD-79638 | biostudies-arrayexpress

Genome-wide mapping of Eset-binding sites and H3K9me3 state in mouse embryonic stem cells

Project description:The histone H3 lysine 9 (H3K9) methyltransferase Eset is an epigenetic regulator critical for the development of the inner cell mass (ICM). Although ICM-derived embryonic stem (ES) cells are normally unable to contribute to the trophectoderm (TE) in blastocysts, we find that depletion of Eset by shRNAs leads to differentiation with the formation of trophoblast-like cells and induction of trophoblast-associated gene expression. Using ChIP-seq analyses, we identified Eset target genes with Eset-dependent H3K9 trimethylation. We confirmed that genes that are preferentially expressed in the TE (Tcfap2a and Cdx2) are bound and repressed by Eset. Single cell PCR analysis shows that the expression of Cdx2 and Tcfap2a is also induced in Eset-depleted morula cells. Importantly, Eset-depleted cells can incorporate into the TE of a blastocyst and subsequently placental tissues. Co-immunoprecipitation and ChIP assays further demonstrates that Eset interacts with Oct4, which in turn recruits Eset to silence these trophoblast-associated genes. Our result suggests that Eset restricts the extraembryonic trophoblast lineage potential of pluripotent cells and links an epigenetic regulator to key cell fate decision through a pluripotency factor. Keywords: Epigenetics Examine Eset-binding sites and compare the H3K9me3 state between Eset knockdown mouse ES cells and control knockdown mouse ES cells.

2009-11-04 | E-GEOD-17642 | biostudies-arrayexpress

Transcriptome profiling of control and FOSL1 knockdown Rcho-1 trophoblast stem (TS) cells

Project description:In hemochorial placentation, trophoblast stem cells differentiate into multiple lineages to aquire specific functions, such as invasive and endocrine phenotype. FOSL1 has been identified as a key regulator for trophoblast differentiation. We used microarray to detail mechanisms underlying FOSL1 signaling pathway in trophoblast differentiation. 3 replicates of differentiated Rcho1 TS cells expressing control shRNA; 3 replicates of differentiated Rcho1 TS cells expressing Fosl1 shRNA

2015-06-30 | E-GEOD-68272 | biostudies-arrayexpress

High-throughput screen for genes predominantly expressed in the ICM of mouse blastocysts by whole mount in situ hybridiz

Project description:We attempted to identify candidate genes that are expressed more highly in the ICM than in TE cells. Mouse ES cells are cultured from the ICM, whereas mouse TS cells are cultured from the TE. Although these cells have been cultured in vitro, they represent the in vitro equivalents of the ICM and TE. Therefore, genes which are expressed more highly in ES than TS in microarray studies were good candidates for genes predominantly expressed in the ICM in blastocysts. We attempted to identify candidate genes that are expressed more highly in the ICM than in TE cells. Mouse ES cells are cultured from the ICM, whereas mouse TS cells are cultured from the TE. Although these cells have been cultured in vitro, they represent the in vitro equivalents of the ICM and TE. Therefore, genes which are expressed more highly in ES than TS in microarray studies were good candidates for genes predominantly expressed in the ICM in blastocysts.

2010-06-09 | E-GEOD-3214 | biostudies-arrayexpress

Arid3a is required for mammalian placenta development

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