Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5942200.fastq.gz | Fastqsanger.gz | |||
| SRR5942201.fastq.gz | Fastqsanger.gz | |||
| SRR5942202.fastq.gz | Fastqsanger.gz | |||
| SRR5942203.fastq.gz | Fastqsanger.gz | |||
| SRR5942204.fastq.gz | Fastqsanger.gz |
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Similar Datasets
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
Project description:The expression of a large proportion of the fission yeast genome changes periodically with the cell cycle. Several key transcription factors have been identified that regulate these oscillating and interdependent waves of gene expression. However, for a significant number of cell cycle-regulated genes the regulator(s) driving these oscillations remain unknown. Cbf11 and Cbf12, the fission yeast CSL transcription factors, have been implicated in the regulation of cell cycle progression, yet the details of their functioning are poorly understood. Using a combination of transcriptome profiling and genome-wide mapping of CSL-DNA interactions we have identified a comprehensive set of CSL-regulated genes. Our data indicate that Cbf11 and Cbf12 contribute directly and indirectly to the regulation of periodically expressed genes in fission yeast. We show that during S phase/cytokinesis Cbf11 directly activates the transcription of several periodic genes required in the cell to prevent catastrophic mitosis. In agreement with these findings, multiple aspects of cell cycle progression are perturbed when CSL cellular levels are genetically manipulated. We have identified Cbf11 as a novel cell cycle phase-specific activator of genes required for proper coordination of cell and nuclear division, and prevention of catastrophic mitosis in fission yeast.
2015-09-18 | E-MTAB-2725 | biostudies-arrayexpress
Project description:Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-J? in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, and p53 activation provides a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effector genes and, in vivo, promotes tumour and stromal cell expansion. Together, the findings support a CAF activation/stromal evolution model under convergent CSL/p53 control. Examination of genome-wide CSL binding sites in primary human dermal fibroblasts usinf two different antibodies against CSL
2015-08-24 | E-GEOD-59942 | biostudies-arrayexpress
Project description:CSL is a key transcription factor, mostly acting as a repressor. While known as main effector of Notch signaling, it can also play Notch-independent functions. Despite the wide interest in CSL, the mechanisms responsible for its own regulation have been little studied. We recently showed that CSL down-modulation in human dermal fibroblasts (HDFs) leads to conversion into cancer associated fibroblasts, which promote keratinocyte tumor development. We show here that levels of CSL gene transcription differ among HDF strains derived from many different individuals, with negative correlation with genes involved in DNA damage/repair. CSL expression in all tested strains is negatively regulated by stress / DNA damaging insults caused by UVA, Reactive Oxygen Species (ROS), smoke extract and doxorubicin treatment. p53, a key effector of the DNA damage response, functions as common negative regulator of CSL gene transcription, through both suppression of CSL promoter activity and, indirectly, through increased p21 expression. CSL was previously shown to bind p53 suppressing its activity. The present findings indicate that p53, in turn, decreases CSL expression, which can serve to enhance p53 activity in the acute response of cells to DNA damaging cancer-threatening conditions.
2016-05-11 | GSE77225 | 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 | GSE102762 | GEO
Project description:Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-Jκ in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, and p53 activation provides a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effector genes and, in vivo, promotes tumour and stromal cell expansion. Together, the findings support a CAF activation/stromal evolution model under convergent CSL/p53 control.
2015-08-24 | GSE59942 | GEO
Project description:Cancer associated fibroblasts (CAFs) play an important role in initiating and promoting epithelial cancers. The specific chromatin modifications involved in CAF activation remain to be elucidated. CSL, a constitutive transcriptional repressor and mediator of canonical Notch signaling, functions as a direct negative regulator of CAF effector genes and suppresses cancer/stromal cell expansion. We find that ATF3, a key stress responsive transcriptional repressor up-regulated in the acute UVA response of skin fibroblasts, is down-modulated in stromal cells of premalignant skin SCC lesions similarly to CSL. Increased ATF3 expression counteracts the consequences of compromised CSL, binding to a large set of overlapping target genes. At low basal levels, ATF3 converges with CSL in negative control of CAF activation, binding to a very small number of genomic loci that encompass mostly non-coding RNAs and pseudogenes. Silencing of ATF3 results in chromatin modifications and Pol II recruitment to many loci to which ATF3 does not bind, which are similarly affected by CSL silencing. The observed changes are of functional significance, as Bet inhibitors, which unlink activated chromatin from the basic transcription apparatus, have opposite effects of ATF3 or CSL silencing on all tested CAF effector genes. They exert a similar impact on clinically-derived CAFs both in vitro and upon topical in vivo treatment. Thus, ATF3 converges with CSL in global chromatin control of CAF activation with their loss eliciting epigenetic changes amenable to cancer and stroma-focused intervention.
2017-06-30 | GSE81404 | GEO
Project description:Cancer associated fibroblasts (CAFs) play an important role in initiating and promoting epithelial cancers. The specific chromatin modifications involved in CAF activation remain to be elucidated. CSL, a constitutive transcriptional repressor and mediator of canonical Notch signaling, functions as a direct negative regulator of CAF effector genes and suppresses cancer/stromal cell expansion. We find that ATF3, a key stress responsive transcriptional repressor up-regulated in the acute UVA response of skin fibroblasts, is down-modulated in stromal cells of premalignant skin SCC lesions similarly to CSL. Increased ATF3 expression counteracts the consequences of compromised CSL, binding to a large set of overlapping target genes. At low basal levels, ATF3 converges with CSL in negative control of CAF activation, binding to a very small number of genomic loci that encompass mostly non-coding RNAs and pseudogenes. Silencing of ATF3 results in chromatin modifications and Pol II recruitment to many loci to which ATF3 does not bind, which are similarly affected by CSL silencing. The observed changes are of functional significance, as Bet inhibitors, which unlink activated chromatin from the basic transcription apparatus, have opposite effects of ATF3 or CSL silencing on all tested CAF effector genes. They exert a similar impact on clinically-derived CAFs both in vitro and upon topical in vivo treatment. Thus, ATF3 converges with CSL in global chromatin control of CAF activation with their loss eliciting epigenetic changes amenable to cancer and stroma-focused intervention.
2017-06-30 | GSE81403 | GEO
Project description:Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-J-kappa in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, with p53 activation providing a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblasts senescence, enhances CAF effector gene expression and, in vivo, promotes stromal and cancer cell expansion. Together, these findings support a CAF activation/stromal evolution model under convergent CSL/p53 control. We used microarrays to detail the global changes in gene expression in human dermal fibroblasts after CSL silencing
2017-12-04 | GSE59847 | GEO