Divergent roles of KLF4 and TFCP2L1 in ground-state naive pluripotency and human primordial germ cell development
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PROVIDER: PRJNA625486 | ENA |
REPOSITORIES: ENA
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Project description:During development, human primordial germ cells (hPGCs) transition through a transcriptional and epigenetic state similar to pre-implantation epiblast cells called naive ground-state pluripotency. Diagnostic transcription factors that define this state include TFAP2C, KLF4, and TFCP2L1, with TFAP2C necessary for both establishment of the naive-like state in hPGC-like cells (hPGCLCs) as well as establishment and self-renewal of naive human embryonic stem cells (hESCs). Here, we show that KLF4 and TFCP2L1 are not required for hPGC specification or establishment of the naive-like state in hPGCLCs. Instead, KLF4 and TFCP2L1 are each required for reversion of primed hESCs to the self-renewing naive ground state. Additionally, TFCP2L1 but not KLF4 function after hPGC specification in the proliferation of the hPGCLC population.
2022-04-30 | GSE148717 | GEO
Project description:Molecular programs involved in embryogenesis are frequently upregulated in oncogenic dedifferentiation and metastasis. However, their precise roles and regulatory mechanisms remain elusive. Here, we showed that CDK1 phosphorylation of TFCP2L1, a pluripotency-associated transcription factor, orchestrated pluripotency and cell-cycling in embryonic stem cells (ESCs) and was aberrantly activated in aggressive bladder cancers (BCs). In murine ESCs, the protein interactome and transcription targets of Tfcp2l1 indicated its involvement in cell-cycle regulation. Tfcp2l1 was phosphorylated at Thr177 by Cdk1, which affected ESC cell-cycle progression, pluripotency, and differentiation. LC-MS was used to characterize thr177 phosphorylation in TFCP2L1 protein obtained by IP experiment and kinase assay. The CDK1-TFCP2L1 pathway was activated in human BC cells, stimulating their proliferation, self-renewal, and invasion. Lack of TFCP2L1 phosphorylation impaired the tumorigenic potency of BC cells in a xenograft model. In patients with BC, high co-expression of TFCP2L1 and CDK1 was associated with unfavorable clinical characteristics including tumor grade, lymphovascular and muscularis propria invasion, and distant metastasis and was an independent prognostic factor for cancer specific survival. These findings demonstrate the molecular and clinical significance of CDK1-mediated TFCP2L1 phosphorylation in stem-cell pluripotency and in the tumorigenic stemness features associated with BC progression.
2019-11-08 | PXD015635 | Pride
Project description:Gene expression analysis of mouse kidney after conditional inactivation of transcription factor Tfcp2l1
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Project description:Mouse embryonic stem cells (ESCs) grown in the 2i (an ERK inhibitor, PD0325901, and a GSK-3b inhibitor, CHIR99021) mimic pluripotent epiblasts in preimplantation blastocysts. ESCs grown in FBS containing medium are more heterogenous in morphology and expression of stem cell factors. Tfcp2l1 is a transcription factor highly expressed in ESCs grown in the 2i medium, suggesting that it plays in important role in ESC biology. To search for the putative role(s) of Tfcp2l1 in ESCs, we plan to use an integrated genomic approach--combing RNA-seq and ChIP-seq--to identify the direct targets of Tfcp2l1 in ESCs. RNA-seq is used to identify the transcripts regulated by Tfcp2l1 in ESCs grown in the 2i medium.
2021-03-01 | GSE159937 | GEO
Project description:Mouse embryonic stem cells (ESCs) grown in the 2i (an ERK inhibitor, PD0325901, and a GSK-3b inhibitor, CHIR99021) mimic pluripotent epiblasts in preimplantation blastocysts. Tfcp2l1 is a transcription factor highly expressed in ESCs grown in the 2i medium, suggesting that it plays in important role in ESC biology. To search for the putative role(s) of Tfcp2l1 in ESCs, we plan to use an integrated genomic approach--combing RNA-seq and ChIP-seq--to identify the direct targets of Tfcp2l1 in ESCs. ChIP-seq is used to identify the genomic bindings sites of Tfcp2l1 in ESCs grown in the 2i medium.
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Project description:We identified Tfcp2l1 binding sites in mouse kidney using Chromatin Immunoprecipitation followed by high-throughput sequencing (ChiP-Seq)
2017-06-19 | GSE87752 | GEO
Project description:Cellular senescence is a stress response mechanism maintaining tissue homeostasis by changing physiological state and inducing irreversible proliferative arrest. It has been reported that hypoxia can bypass senescence and extend lifespan of naïve primary cells, mainly, by the decrease in oxidative damage. However, it is unclear how hypoxia can promote the evasion of senescence and promote cell immortalization prior to malignant transformation. We observed that the lifespan of MEFs is increased when they are cultured in hypoxia, reducing the expression of p16INK4a, p15INK4b and p21Cip1. In transcriptional genetic screenings, we found that proliferating naïve MEFs in hypoxia overexpress Tfcp2l1, which is a main regulator of pluripotency and self-renewal in embryonic stem cells, ESCs, as well as stemness-associated genes like Oct3/4, Sox2, Nanog. Tfcp2l1 expression is lost during culture in normoxia. The expression of Tfcp2l1 in hypoxia seems to be regulated by Hif1α and only when it is overexpressed at similar levels to those induced physiologically by hypoxia it increases lifespan of MEFs and promotes overexpression of stemness-associated genes. In Chip-seq experiments, we found that Tfcp2l1 binds and activate the expression of genes which regulate proliferation, which in many cases, are also related to stem cell properties, such as Sox2, Sox9 and Tgfa. Additionally, Tfcp2l1 can replicate the effect of hypoxia increasing cellular reprogramming and its expression correlates positively with the expression of Nanog and negatively with p21Cip1 and p16INK4a. Altogether, our data suggests that the activation of Tfcp2l1 by hypoxia could be relevant in the immortalization prior to malignant transformation, facilitating tumorigenesis and dedifferentiation of cells.
2024-02-22 | GSE173648 | GEO
Project description:We identified genes regulated by Tfcp2l1 overexpression in Rat Metanephric Mesenchyme
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Project description:Current human pluripotent stem cells lack the transcription factor circuitry that governs the ground state of mouse embryonic stem cells (ESC). Here we report that short-term expression of two components, NANOG and KLF2, is sufficient to ignite other elements of the network and reset the human pluripotent state. Inhibition of ERK and protein kinase C signalling sustains a transgene-independent rewired state. Reset cells self-renew continuously without ERK signalling, are phenotypically stable and karyotypically intact. They differentiate in vitro and form teratomas in vivo. Metabolism is reprogrammed in reset cells with activation of mitochondrial respiration as in ESC. DNA methylation is dramatically reduced and transcriptome state is globally realigned across multiple cell lines. Depletion of ground state transcription factors, TFCP2L1 or KLF4 has marginal impact on conventional human pluripotent stem cells, but collapses the reset state. These findings demonstrate feasibility of installing and propagating functional control circuitry for ground state pluripotency in human cells. DNA methylation analysis in Conventional and Reset human embryonic stem cells by whole genome bisulfite sequencing, in triplicate, using the Illumina platform
2014-09-10 | E-GEOD-60945 | biostudies-arrayexpress
Project description:Purpose:The goals of this study are to analyze the candidate genes motified by Tfcp2l1 overexpression to regulated the human embryonic stem cell (ESC) self-renewal through RNA-seq approach.
2018-06-06 | GSE115075 | GEO