Hypoxia-induced expression of Tfcp2l1 promotes cell immortalization by enhancing cellular reprogramming
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ABSTRACT:
PROVIDER: PRJNA726529 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14369943_1.fastq.gz | Fastqsanger.gz | |||
| SRR14369943_2.fastq.gz | Fastqsanger.gz | |||
| SRR14369944_1.fastq.gz | Fastqsanger.gz | |||
| SRR14369944_2.fastq.gz | Fastqsanger.gz | |||
| SRR27164910_1.fastq.gz | Fastqsanger.gz |
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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:Cellular senescence is a stress response mechanism that induces proliferative arrest. Hypoxia can bypass senescence and extend the lifespan of primary cells, mainly by decreasing oxidative damage. However, how hypoxia promotes these effects prior to malignant transformation is unknown. Here we observed that the lifespan of mouse embryonic fibroblasts (MEFs) is increased when they are cultured in hypoxia by reducing the expression of p16INK4a, p15INK4b and p21Cip1. We found that proliferating MEFs in hypoxia overexpress Tfcp2l1, which is a main regulator of pluripotency and self-renewal in embryonic stem cells, as well as stemness genes including Oct3/4, Sox2 and Nanog. Tfcp2l1 expression is lost during culture in normoxia, and its expression in hypoxia is regulated by Hif1α. Consistently, its overexpression in hypoxic levels increases the lifespan of MEFs and promotes the overexpression of stemness genes. ATAC-seq and Chip-seq experiments showed that Tfcp2l1 regulates genes that control proliferation and stemness such as Sox2, Sox9, Jarid2 and Ezh2. Additionally, Tfcp2l1 can replicate the hypoxic effect of increasing cellular reprogramming. Altogether, our data suggest that the activation of Tfcp2l1 by hypoxia contributes to immortalization prior to malignant transformation, facilitating tumorigenesis and dedifferentiation by regulating Sox2, Sox9, and Jarid2.
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Project description:Gene expression analysis of mouse kidney after conditional inactivation of transcription factor Tfcp2l1
2017-06-19 | GSE85325 | 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:To investigate the genes and pathways regulated by TFCP2L1 in thyroid cancer cells, we established TFCP2L1-overexpressing TPC1 cell line and performed RNA sequencing for further study.
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Project description:The overexpression of defined transcription factors in somatic cells results in their reprogramming into induced pluripotent stem (iPS) cells. The extremely low efficiency and slow kinetics of in vitro reprogramming suggest that further rare events are required to generate iPS cells. The nature and identity of these events, however, remain elusive. We noticed that the reprogramming potential of primary murine fibroblasts into iPS cells decreases after serial passaging and the concomitant onset of senescence. Consistent with the notion that loss of replicative potential provides a barrier for reprogramming, here we show that cells with low endogenous p19(Arf) (encoded by the Ink4a/Arf locus, also known as Cdkn2a locus) protein levels and immortal fibroblasts deficient in components of the Arf-Trp53 pathway yield iPS cell colonies with up to threefold faster kinetics and at a significantly higher efficiency than wild-type cells, endowing almost every somatic cell with the potential to form iPS cells. Notably, the acute genetic ablation of Trp53 (also known as p53) in cellular subpopulations that normally fail to reprogram rescues their ability to produce iPS cells. Our results show that the acquisition of immortality is a crucial and rate-limiting step towards the establishment of a pluripotent state in somatic cells and underscore the similarities between induced pluripotency and tumorigenesis.
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Project description:Gene expression at various stages of immortalization
2016-05-12 | GSE46931 | 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. 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.
2021-03-01 | GSE159877 | GEO
Project description:Breast cancer represents the most prevalent form of malignant tumors among women. Despite the existence of numerous therapeutic methods, a significant portion of patients face a poor prognosis, highlighting the urgency in identifying new remedial targets. Here, we for the first time demonstrated that the CP2 family member TFCP2L1, a classical marker of embryonic stem cell maintenance, as a tumor suppressor in breast cancer. Patients with breast cancer have poorer prognoses when TFCP2L1 is expressed highly. Consistently, the expression of TFCP2L1 is higher in normal breast cells than those in breast cancer cell lines. Gain- and loss-of-function and xenograft tumor assay showed that overexpression of TFCP2L1 significantly inhibited both the proliferation and migration of breast cancer cells in vivo and in vitro. Conversely, the knockdown of TFCP2L1 promoted the proliferation and migration of breast cancer cells. Mechanistically, we found that TFCP2L1 suppresses breast cancer progression by directly inhibiting the expression of glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis. Therefore, inhibition of GPX4 by RSL3, an inducer of ferroptosis was able to promote the function of TFCP2L1 in breast cancer cells. On the other hand, transcriptome high-throughput exhibited that TFCP2L1 negatively regulated the activity of PI3K/AKT signaling pathway. Administration of SC79, an AKT activator, was capable of partially restoring the negative effects of TFCP2L1 on GPX4 transcription. Together, TFCP2L1 functions by directly or indirectly regulating GPX4-mediated ferroptosis, and may serve as a novel biomarker and potential therapeutic target for breast cancer.
2024-07-30 | GSE270578 | GEO