Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Chromatin interaction and histone mark signatures associated with TBXT expression in metastatic lung cancer

ABSTRACT: The role of TBXT in cancer formation and progression is well studied, as is its expression regulation during embryonic development, but how its expression is activated and maintained in lung cancers remains elusive. Circularized chromosome capture combined with sequencing (4C-seq) was employed to analyze physical chromatin interactions with the TBXT promoter in the lung cancer cell line H460, a high TBXT expressing cell line, compared to H358 and A549, which do not express TBXT. Our analysis identified distinct patterns of potential cis-regulatory elements (pCREs) associated with the TBXT promoter, with increased near-cis pCRE enrichment in TBXT-expressing cells. Integration of pCREs with epigenetic histone modification revealed TBXT expression-specific regulatory landscapes, suggesting a role for epigenetic mechanisms in TBXT control. Two unique pCREs in TBXT-expressing H460 cells enriched with active histone mark H3K27ac, harbored binding sites for transcription factors of the forkhead box, zinc finger, and musculoaponeurotic fibrosarcoma families that are linked to cancer metastasis. Our findings shed light on the intricate control of TBXT expression in lung cancers, pointing to specific DNA elements and regulatory proteins that may be involved. This knowledge paves the way for understanding TBXT expression dynamics at the onset and progression of metastatic cancers and ultimately developing new therapeutic strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274316 | GEO | 2025/03/26

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma

Project description:Aberrant expression of the embryonal transcription factor TBXT (also known as brachyury) drives chordoma, a rare spinal neoplasm with no effective drug therapies. The gene network regulated by TBXT is poorly understood, and strategies to disrupt its abnormal activity for therapeutic purposes are lacking. Here, we developed TBXT-targeted designed ankyrin repeat proteins (T-DARPins) that selectively bind TBXT, inhibiting its binding to DNA and expression. In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced morphologic changes indicative of senescence and differentiation. Combining T-DARPin-mediated TBXT inhibition with transcriptomic and proteomic analyses, we determined the TBXT regulome in chordoma cells, which comprises in particular networks involved in cell cycle regulation, DNA replication and repair, embryonal cell identity, metabolic processes, and interferon response. The analysis of selected TBXT regulome components provided new insights into chordoma biology, such as the strong upregulation of IGFBP3 upon TBXT inhibition to fine-tune part of TBXT’s downstream effectors. Finally, we assigned each TBXT regulome member a druggability status to create a resource for future translational studies and found high interferon response signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with strong sensitivity to clinically approved JAK2 inhibitors. These findings demonstrate the potential of DARPins to investigate the function of nuclear proteins to understand the regulatory networks of cancers driven by aberrant transcription factor activity, including novel entry points for targeted therapies that warrant testing in patients.

2025-07-31 | PXD055982 | Pride

Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma

Project description:The embryonic transcription factor TBXT (brachyury) drives chordoma, a spinal neoplasm without effective drug therapies. TBXT’s regulatory network is poorly understood, and strategies to disrupt its activity for therapeutic purposes are lacking. We developed designed ankyrin repeat proteins that block TBXT-DNA binding (T-DARPins). In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced signs of senescence and differentiation. Transcriptomic and proteomic analyses identified gene networks involved in cell cycle regulation, embryonic cell identity, and interferon response and revealed features of regulome components, such as susceptibility to pharmacologic inhibition and the fine-tuning of TBXT downstream effectors through IGFBP3. Finally, we found high interferon signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with sensitivity to JAK2 inhibitors. These findings demonstrate the potential of DARPins for probing nuclear proteins to understand the regulatory networks of transcription factor-driven cancers, including entry points for therapies that warrant testing in patients.

2025-07-31 | GSE276715 | GEO

Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death (ChIP-seq)

Project description:Expression of the transcription factor brachyury (TBXT) is normally restricted to the embryo and its silencing is epigenetically regulated. TBXT promotes mesenchymal transition in a subset of common carcinomas, and in chordoma, a rare cancer showing notochordal differentiation, TBXT acts as a putative oncogene: we hypothesised that TBXT expression could be controlled through epigenetic inhibition to promote chordoma cell death. Screening of five human chordoma cell lines revealed that pharmacological inhibition of the histone 3 lysine 27 demethylases KDM6A (UTX) and KDM6B (JMJD3) leads to cell death. This effect was phenocopied by the dual genetic inactivation of KDM6A/B using CRISPR/Cas9. Inhibition of KDM6A/B using a novel compound, KDOBA67, led to a genome-wide increase in repressive H3K27me3 marks, with concomitant reduction in H3K27ac, H3K9ac and H3K4me3 active marks. We show that TBXT is a KDM6A/B target gene, and that changes in the chromatin at TBXT following KDOBA67 treatment were associated with a reduction in TBXT protein levels in all models tested, including primary patient-derived cultures. KDOBA67 downregulated also the expression of a network of transcription factors critical for chordoma survival, whereas upregulated pathways were dominated by ATF4-driven stress and pro-apoptotic responses in all models. Blocking the AFT4-stress response did not prevent the suppression of TBXT and induction of cell death, but viability was increased by ectopic overexpression of TBXT, therefore implicating TBXT as potential therapeutic target of H3K27 demethylases inhibitors. Our work highlights how knowledge of normal processes in fetal development can provide insight into tumourigenesis and identify novel therapeutic approaches.

2020-09-01 | GSE150600 | GEO

Lung cell lines grown in 2D and 3D

Project description:Comparison of gene expression data between cell lines grown on 2D tissue culture plastic or 3D matrigel A427, A549, H23, H358, H460, H661, H1437, and H1703 cells were compared

2020-09-26 | GSE158597 | GEO

Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death [RNA-Seq I]

Project description:The expression of transcription factor brachyury (TBXT) is normally restricted to embryonic development and its silencing after mesoderm development is epigenetically regulated. In chordoma, a rare tumour of notochordal differentiation, TBXT acts as a putative oncogene, and we hypothesised that its expression could be contolled through epigenetic inhibition. Screening of five chordoma cell lines revealed that inhibitors of the histone 3 lysine 27 demethylases KDM6A (UTX) and KDM6B (Jmjd3) reduce TBXT expression and lead to cell death, findings validated in primary patient-derived culture systems. Pharmacological inhibition was phenocopied by genetic inactivation of KDM4/B using CRISPR/Cas9. Transcriptional profiles in response to a novel KDM6A/B inhibitor, KDOBA67, revealed downregulation of critical genes and transcription factor networks for chordoma survival pathways, characterised by paired and homeobox genes, whereas upregulated pathways are dominated by stress, cell cycle and pro-apoptotic response pathways. This study supports previous data showing that the function of TBXT is essential for maintaining notochord cell fate and function and provides further evidence that TBXT is an oncogenic driver in chordoma. The data suggest that TBXT can potentially be targeted therapeutically by modulating epigenetic control mechanisms such as H3K27 demethylases.

2020-09-01 | GSE119424 | GEO

Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death [RNA-Seq III]

2020-09-01 | GSE133308 | GEO

Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death [RNA-Seq II]

2020-09-01 | GSE120210 | GEO

The malignant trajectory from the notochord to chordoma and the role of the TBXT rs2305089 germline single nucleotide polymorphism

Project description:The rare bone cancer chordoma and its putative precursor the Benign Notochordal Cell Tumor (BNCT) express the notochordal transcription factor, TBXT. The aim of this study was to elucidate the role of rs2305089 germline single nucleotide polymorphism in TBXT in the pathogenesis of chordoma. A radiological and genotyping association study demonstrated that BNCTs are associated with chordomas (P<0.001) and with the rs2305089 polymorphism (P=0.002). We then engineered mesoderm/notochord models which differed only by their rs2305089 genotype. Expression of TBXT was higher and the gene regulatory network activated by TBXT was enriched in heterozygous compared to wild type cell lines. Heterozygous cell lines displayed enrichment of Wnt/beta-catenin and epithelial mesenchymal transition pathways while wild type cell lines were enriched for metabolic pathways and MTORC1 signalling. Moreover, the variant A allele induced faster cell migratory capacity together with changes in the expression of endoplasmic reticulum and intracellular transport mediators, thus suggesting that rs2305089 regulates notochord vacuoles as lysosome-related organelles in the aberrant regression of the notochord. In conclusion, we show for the first time that the rs2305089 variant allele is associated not only with chordoma but also with the BNCT and provide functional evidence that this SNP regulates notochordal cell differentiation in the pathogeneis of BNCTs and chordomas.

2025-03-28 | GSE277707 | GEO

TBXT dose sensitivity and the decoupling of mesoderm specification from EMT progression in 2D human gastruloids

Project description:In the nascent mesoderm, levels of Brachyury (TBXT) expression must be precisely regulated to ensure cells exit the primitive streak and pattern the anterior-posterior axis, but how this varying dosage informs morphogenesis is not well understood. In this study, we define the transcriptional consequences of TBXT dose during early gastrulation using human induced pluripotent stem cell (hiPSC)-based models of early gastrulation and mesoderm differentiation. Multiomic single-nucleus RNA and single-nucleus ATAC sequencing reveal that TBXT is required for the temporal progression of epithelial-to-mesenchymal transition (EMT) in a dose-dependent manner and that this transition occurs independently of the acquisition of mesodermal identity. These results demonstrate that EMT can be decoupled from mesoderm development in the early gastrula and shed light on the mechanisms underlying human embryogenesis.

2024-02-14 | GSE245998 | GEO

RNA sequencing of control and TBXT-depleted human NMP-like axial progenitors

Project description:A Tetracycline (Tet)-inducible TBXT shRNA human embryonic stem cell (hESC) line was treated with WNT and FGF agonists in the presence and absence of Tet for three days to generate NMP-like axial progenitors

2021-09-23 | GSE184620 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data