Dual role of CSL (RBP-Jk) and NOTCH1 in cancer-associated fibroblast genome stability and expansion [RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA451482 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7057680.fastq.gz | Fastqsanger.gz | |||
| SRR7057690.fastq.gz | Fastqsanger.gz | |||
| SRR7057681.fastq.gz | Fastqsanger.gz | |||
| SRR7057691.fastq.gz | Fastqsanger.gz | |||
| SRR7057682.fastq.gz | Fastqsanger.gz |
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Project description:Dual role of CSL (RBP-Jk) and NOTCH1 in CAF
| PRJNA453139 | ENA
Project description:Genomic instability is a hallmark of cancer. Whether or not it also occurs in cancer-associated fibroblasts (CAFs) is a question of importance for the cancer/stromal cell co-evolution process. We find that DNA damage, telomere shortening and chromosome fusions occur at early times of CAF activation, as triggered by silencing of the CSL/RBP-J-κ gene in primary human dermal fibroblasts (HDFs) from multiple individuals. Similar alterations occur in skin Squamous Cell Carcinoma (SCC) - derived CAFs, in which CSL is down-modulated, versus HDFs from unaffected skin of the same patients. Mechanistically, CSL is part of a telomere protective complex with UPF1, KU70, and KU80 proteins, which fail to bind to telomeres in the absence of CSL. In CAFs, persistent genomic instability is associated with frequent amplification and overexpression of NOTCH1 gene, which is required to suppress DNA damage-induced ATM/P53 activation and growth arrest. These findings are of translational significance as, in an orthotopic model of skin SCC, genetic or pharmacological suppression of NOTCH1 activity suppresses cancer/stromal cell proliferation and expansion.
2019-09-11 | GSE113542 | GEO
Project description:Interaction of the Kaposi’s sarcoma-associated herpesvirus (KSHV) Rta protein with the cellular Notch signaling effector, Recombination Signaling Protein (RBP)-Jk (aka CSL and CBF-1), is essential for viral reactivation from latency. We previously showed that Rta binds to a DNA motif repeated in the viral Mta promoter (called “CANT” or Rta-c) to stimulate RBP-Jk DNA binding, and distinguished Rta from the activated Notch-1 protein. To determine whether Rta’s mechanism would apply generally to other viral promoters, we employed chromatin immunoprecipitation/deep sequencing (ChIP/Seq) to identify Rta and RBP-Jk binding sites across the KSHV genome. We show that RBP-Jk binds nearly exclusively to unique genome sites during latency and reactivation. Many, but not all, reactivation-specific RBP-Jk peaks were associated with Rta bound to single Rta-c motifs. Other motifs that were over-represented with stimulated RBP-Jk DNA binding including those for the cellular DNA binding proteins BCL11A, MNT, MAF B, and TCF12. Four of the top seven motifs that were most over-represented with inhibition of RBP-Jk DNA binding were putative binding sites for the Pit/Oct/Unc (POU) family of proteins, including POU3F3 (Oct-8) and POU5F1 (Oct-4). Interestingly, two other POU motifs, including one for the POU2F1 (Oct-1) protein, are associated with inhibition of RBP-Jk DNA binding unless Rta bound to a nearby Rta-c motif. The relative distances between the Rta-c, POU, and RBP-Jk motifs were conserved at reactivation-specific RBP-Jk peaks in three promoters that Rta transactivated, and the Rta-c and Oct-1 motifs overlapped in two of those. The proximity of the Rta-c/Oct-1 motif to an RBP-Jk motif is critical for Rta transactivation of the ORF50AS/KbZIP promoter, and knockdown of Oct-1 protein debilitated reactivation and production of infectious virus. Our data suggest a broad role for POU proteins in regulating DNA binding of RBP-Jk and its associated transactivators.
2019-07-14 | GSE122752 | GEO
Project description:It is currently unclear whether tissue changes surrounding multifocal epithelial tumors are a cause or consequence of cancer. Here, we provide evidence that loss of mesenchymal Notch/CSL signaling causes tissue alterations, including stromal atrophy and inflammation, which precede and are potent triggers for epithelial tumors. Mice carrying a mesenchymal-specific deletion of CSL/RBP-JK, a key Notch effector, exhibit spontaneous multifocal keratinocyte tumors that develop after dermal atrophy and inflammation. CSL-deficient dermal fibroblasts promote increased tumor cell proliferation through up-regulation of c-Jun and c-Fos expression and consequently higher levels of diffusible growth factors, inflammatory cytokines, and matrix remodeling enzymes. In human skin samples, stromal fields adjacent to cutaneous squamous cell carcinomas and multifocal premalignant actinic keratosis lesions exhibit decreased Notch/CSL signaling and associated molecular changes. Importantly, these changes in gene expression are also induced by UVA, a known environmental cause of cutaneous field cancerization and skin cancer. We used microarrays to detail the global changes in gene expression in dermal fibroblasts with in vivo and in vitro deletion of the RBP-Jk gene, compared to corresponding controls Global changes in gene expression in dermal fibroblasts with in vivo and in vitro deletion of the RBP-Jk gene were assessed, in parallel with the corresponding controls
2012-06-11 | E-GEOD-36359 | biostudies-arrayexpress
Project description:It is currently unclear whether tissue changes surrounding multifocal epithelial tumors are a cause or consequence of cancer. Here, we provide evidence that loss of mesenchymal Notch/CSL signaling causes tissue alterations, including stromal atrophy and inflammation, which precede and are potent triggers for epithelial tumors. Mice carrying a mesenchymal-specific deletion of CSL/RBP-JK, a key Notch effector, exhibit spontaneous multifocal keratinocyte tumors that develop after dermal atrophy and inflammation. CSL-deficient dermal fibroblasts promote increased tumor cell proliferation through up-regulation of c-Jun and c-Fos expression and consequently higher levels of diffusible growth factors, inflammatory cytokines, and matrix remodeling enzymes. In human skin samples, stromal fields adjacent to cutaneous squamous cell carcinomas and multifocal premalignant actinic keratosis lesions exhibit decreased Notch/CSL signaling and associated molecular changes. Importantly, these changes in gene expression are also induced by UVA, a known environmental cause of cutaneous field cancerization and skin cancer. We used microarrays to detail the global changes in gene expression in dermal fibroblasts with in vivo and in vitro deletion of the RBP-Jk gene, compared to corresponding controls
2012-06-12 | GSE36359 | GEO
Project description:Gene expression programs depend on sequence-specific DNA binding transcription factors, but the mechanisms that control the selective binding of these factors in a chromosomal and genomic context remain enigmatic. Here, we show that two master regulators of B-cell fate, namely EBF1 and RBP-jk, show variable genome-wide chromosome distribution in two related B-lymphocyte lines carrying different forms of Epstein-Barr Virus (EBV) latency. The latency-type specific EBV-encoded EBNA2 colocalized with RBP-jk and EBF1 at induced binding sites. Colocalization of EBF1, RBP-jk, and EBNA2 correlated with transcriptional activation. Conditional expression or repression of EBNA2 lead to a rapid alteration in RBP-jk and EBF1 binding. Biochemical and shRNA depletion studies provide evidence for cooperative assembly at co-occupied sites. These findings reveal that non-DNA binding cofactors can facilitate combinatorial interactions to induce new patterns of transcription factor occupancy and gene programming Examination of EBNA2/EBF1/EBP-jk binding in MutuI and LCL cell lines
2015-12-16 | E-GEOD-75503 | biostudies-arrayexpress
Project description:Gene expression programs depend on sequence-specific DNA binding transcription factors, but the mechanisms that control the selective binding of these factors in a chromosomal and genomic context remain enigmatic. Here, we show that two master regulators of B-cell fate, namely EBF1 and RBP-jk, show variable genome-wide chromosome distribution in two related B-lymphocyte lines carrying different forms of Epstein-Barr Virus (EBV) latency. The latency-type specific EBV-encoded EBNA2 colocalized with RBP-jk and EBF1 at induced binding sites. Colocalization of EBF1, RBP-jk, and EBNA2 correlated with transcriptional activation. Conditional expression or repression of EBNA2 lead to a rapid alteration in RBP-jk and EBF1 binding. Biochemical and shRNA depletion studies provide evidence for cooperative assembly at co-occupied sites. These findings reveal that non-DNA binding cofactors can facilitate combinatorial interactions to induce new patterns of transcription factor occupancy and gene programming
2015-12-16 | GSE75503 | GEO
Project description:Gene expression programs depend on sequence-specific DNA binding transcription factors, but the mechanisms that control the selective binding of these factors in a chromosomal and genomic context remain enigmatic. Here, we show that two master regulators of B-cell fate, namely EBF1 and RBP-jk, show variable genome-wide chromosome distribution in two related B-lymphocyte lines carrying different forms of Epstein-Barr Virus (EBV) latency. The latency-type specific EBV-encoded EBNA2 colocalized with RBP-jk and EBF1 at induced binding sites. Colocalization of EBF1, RBP-jk, and EBNA2 correlated with transcriptional activation. Conditional expression or repression of EBNA2 lead to a rapid alteration in RBP-jk and EBF1 binding. Biochemical and shRNA depletion studies provide evidence for cooperative assembly at co-occupied sites. These findings reveal that non-DNA binding cofactors can facilitate combinatorial interactions to induce new patterns of transcription factor occupancy and gene programming
2015-12-16 | GSE75385 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-09-11 | GSE113578 | GEO
Project description:Down-modulation or loss-of-function mutations of the Notch 1 and 2 genes are associated with development of squamous cell carcinoma (SCC), a very frequent and therapy-resilient malignancy in skin, head/neck (H/N), lung and other surface epithelia. In this context, surprisingly little is known on the role of CSL (RBP-Jk), key effector of canonical Notch signaling endowed with intrinsic transcription repressive function. CSL expression is decreased in upper epidermal layers and differentiating primary human keratinocytes (HKCs), while it is up-regulated in premalignant and malignant SCC lesions and SCC cell lines from skin, Head/Neck and lung. Increased CSL levels enhance proliferation and self-renewal potential of HKCs and SCC cells, while its silencing induces growth arrest and apoptosis. In vivo, SCC cells with increased CSL levels give rise to rapidly expanding tumors, while upon CSL silencing they form smaller and more differentiated tumors with enhanced inflammatory infiltrate. Global transcriptomic analysis of HKC and SCC cells plus/minus CSL silencing reveals major modulation of apoptotic, cell cycle and pro-inflammatory genes, with no significant association with Notch or keratinocyte differentiation gene signatures. KDM6B, a histone demethylase gene with highly context dependent functions, is a direct CSL negative target, with an inverse role of CSL in HKC and SCC self-renewal and tumorigenesis, with IL6 as a target of likely significance. CSL / KDM6B protein expression could be used as biomarkers of SCC development and novel indicators of cancer treatment.
2017-12-15 | GSE102761 | GEO