Epigenetic misactivation of a distal developmental enhancer drives SOX2 overexpression in multiple cancer subtypes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA547640 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15865590_1.fastq.gz | Fastqsanger.gz | |||
| SRR15865590_2.fastq.gz | Fastqsanger.gz | |||
| SRR15865591_1.fastq.gz | Fastqsanger.gz | |||
| SRR15865591_2.fastq.gz | Fastqsanger.gz | |||
| SRR15865592_1.fastq.gz | Fastqsanger.gz |
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Project description:We have investigated a distal regulatory region that drives SOX2 overexpression in multiple cancer subtypes
2023-03-16 | GSE132344 | GEO
Project description:We report the effect on genome-wide gene expression after deletion of an enhancer region downstream of Sox2 in F1 ES cells. The Sox2 transcription factor must be robustly transcribed in embryonic stem (ES) cells to maintain pluripotency. Reporter assays reveal novel enhancers, including two enhancers over 100 kb downstream (SRR107 and SRR111) which, through the formation of chromatin loops, localise to the Sox2 promoter in ES cells. Using CRISPR/Cas9 we deleted a region containing these two enhancers, which we term the Sox2 control region (SCR). This deletion revealed that the SCR is required for Sox2 transcription in ES cells. Furthermore, homozygous deletion of this distal Sox2 control region (SCR) caused significant reduction in Sox2 mRNA and protein levels, loss of ES cell colony morphology, genome-wide changes in gene expression and impaired neuroectodermal formation upon spontaneous differentiation to embryoid bodies. Together these data identify a distal control region essential for Sox2 transcription in ES cells. Examination of PolA+ RNA after heterozygous and homozygous enhancer deletion in F1 ES cells (M. musculus129 x M. castaneus).
2014-11-19 | E-GEOD-58339 | biostudies-arrayexpress
Project description:We report the effect on genome-wide gene expression after deletion of an enhancer region downstream of Sox2 in F1 ES cells. The Sox2 transcription factor must be robustly transcribed in embryonic stem (ES) cells to maintain pluripotency. Reporter assays reveal novel enhancers, including two enhancers over 100 kb downstream (SRR107 and SRR111) which, through the formation of chromatin loops, localise to the Sox2 promoter in ES cells. Using CRISPR/Cas9 we deleted a region containing these two enhancers, which we term the Sox2 control region (SCR). This deletion revealed that the SCR is required for Sox2 transcription in ES cells. Furthermore, homozygous deletion of this distal Sox2 control region (SCR) caused significant reduction in Sox2 mRNA and protein levels, loss of ES cell colony morphology, genome-wide changes in gene expression and impaired neuroectodermal formation upon spontaneous differentiation to embryoid bodies. Together these data identify a distal control region essential for Sox2 transcription in ES cells.
2014-11-19 | GSE58339 | GEO
Project description: Not available
| S-EPMC10602899 | biostudies-literature
Project description:The pluripotency of embryonic stem cells (ESCs) is maintained by a small group of master transcription factors including Oct4, Sox2 and Nanog. These core factors form a regulatory circuit controlling the transcription of a number of pluripotency factors including themselves. Although a lot of previous studies have identified key factors regulating this core network in trans, the contribution of cis-regulatory DNA sequences on the transcription of these key pluripotency factors remains elusive. We analyzed epigenomic data within the 1.5 Mb gene-desert regions around Sox2 gene and predicted only one 13kb-long enhancer located 100kb downstream of Sox2 in mouse ES cells. This enhancer is occupied by Oct4, Sox2, Nanog, and mediator complex and forms a long-range DNA looping to Sox2 locus. We hypothesized that this enhancer is critical for Sox2 gene expression and tested this hypothesis by deleting this entire 13-kb enhancer with a simple highly-efficient double-excision CRISPR strategy. Allele-specific of Sox2 transcripts in heterozygous enhancer-deletion clones showed that the enhancer affects expression through a cis-acting mechanism. Strikingly, although this distal enhancer is not conserved in other mammals including human, it is responsible for over 90% of Sox2 expression in mouse ESCs. Taken together, our results provide direct evidence that in mouse ESCs, Sox2 transcription is primarily driven by a species-specific distal enhancer, which may provide new perspectives explaining the physiological difference between human and mouse ES cells. This dataset include ChIP-seq of H3K4me3 and H3K27ac in a hybrid mouse ES cells (F123). H3K27ac in J1 mouse ES cells. And RNA-seq in F123 mESCs with complete Sox2 enhancer deletion or enhancer haploinsufficient clones.
2014-12-09 | E-GEOD-60763 | biostudies-arrayexpress
Project description:The pluripotency of embryonic stem cells (ESCs) is maintained by a small group of master transcription factors including Oct4, Sox2 and Nanog. These core factors form a regulatory circuit controlling the transcription of a number of pluripotency factors including themselves. Although a lot of previous studies have identified key factors regulating this core network in trans, the contribution of cis-regulatory DNA sequences on the transcription of these key pluripotency factors remains elusive. We analyzed epigenomic data within the 1.5 Mb gene-desert regions around Sox2 gene and predicted only one 13kb-long enhancer located 100kb downstream of Sox2 in mouse ES cells. This enhancer is occupied by Oct4, Sox2, Nanog, and mediator complex and forms a long-range DNA looping to Sox2 locus. We hypothesized that this enhancer is critical for Sox2 gene expression and tested this hypothesis by deleting this entire 13-kb enhancer with a simple highly-efficient double-excision CRISPR strategy. Allele-specific of Sox2 transcripts in heterozygous enhancer-deletion clones showed that the enhancer affects expression through a cis-acting mechanism. Strikingly, although this distal enhancer is not conserved in other mammals including human, it is responsible for over 90% of Sox2 expression in mouse ESCs. Taken together, our results provide direct evidence that in mouse ESCs, Sox2 transcription is primarily driven by a species-specific distal enhancer, which may provide new perspectives explaining the physiological difference between human and mouse ES cells.
2014-12-09 | GSE60763 | GEO
Project description:Sox2 expression is regulated by a distal enhancer cluster known as the Sox2 Control Region (SCR). Although Sox2 and the SCR exhibit strong interactions in chromosome conformation capture experiments, acute depletion of cohesin only mildly affects Sox2 transcription. Here we show that continuous loop extrusion, but not stalling of cohesin at CTCF sites is involved in the maintenance of the Sox2-SCR loop. While depletion of cohesin or CTCF has only a mild impact on Sox2 gene expression, stabilizing cohesin on the DNA by depleting the cohesin release factor WAPL results in a rapid decrease in expression. Furthermore, using genome editing we show that a weak enhancer located downstream from the Sox2 gene renders Sox2 expression insensitive to the loss of cohesin stalling at CTCF sites. Finally, through targeted and pleiotropic inhibition of the SCR we demonstrate that the Sox2-SCR loop is a multi-component system that depends on cohesin-mediated loop extrusion and enhancer-associated factors. Together, our findings highlight the intricate interplay between enhancer activity and loop extrusion in the establishment and maintenance of chromatin loops in the Sox2 locus.
2026-04-15 | GSE306300 | GEO
Project description:Sox2 expression is regulated by a distal enhancer cluster known as the Sox2 Control Region (SCR). Although Sox2 and the SCR exhibit strong interactions in chromosome conformation capture experiments, acute depletion of cohesin only mildly affects Sox2 transcription. Here we show that continuous loop extrusion, but not stalling of cohesin at CTCF sites is involved in the maintenance of the Sox2-SCR loop. While depletion of cohesin or CTCF has only a mild impact on Sox2 gene expression, stabilizing cohesin on the DNA by depleting the cohesin release factor WAPL results in a rapid decrease in expression. Furthermore, using genome editing we show that a weak enhancer located downstream from the Sox2 gene renders Sox2 expression insensitive to the loss of cohesin stalling at CTCF sites. Finally, through targeted and pleiotropic inhibition of the SCR we demonstrate that the Sox2-SCR loop is a multi-component system that depends on cohesin-mediated loop extrusion and enhancer-associated factors. Together, our findings highlight the intricate interplay between enhancer activity and loop extrusion in the establishment and maintenance of chromatin loops in the Sox2 locus.
2026-04-15 | GSE306299 | GEO
Project description:Sox2 expression is regulated by a distal enhancer cluster known as the Sox2 Control Region (SCR). Although Sox2 and the SCR exhibit strong interactions in chromosome conformation capture experiments, acute depletion of cohesin only mildly affects Sox2 transcription. Here we show that continuous loop extrusion, but not stalling of cohesin at CTCF sites is involved in the maintenance of the Sox2-SCR loop. While depletion of cohesin or CTCF has only a mild impact on Sox2 gene expression, stabilizing cohesin on the DNA by depleting the cohesin release factor WAPL results in a rapid decrease in expression. Furthermore, using genome editing we show that a weak enhancer located downstream from the Sox2 gene renders Sox2 expression insensitive to the loss of cohesin stalling at CTCF sites. Finally, through targeted and pleiotropic inhibition of the SCR we demonstrate that the Sox2-SCR loop is a multi-component system that depends on cohesin-mediated loop extrusion and enhancer-associated factors. Together, our findings highlight the intricate interplay between enhancer activity and loop extrusion in the establishment and maintenance of chromatin loops in the Sox2 locus.
2026-04-15 | GSE306298 | GEO
Project description:Sox2 expression is regulated by a distal enhancer cluster known as the Sox2 Control Region (SCR). Although Sox2 and the SCR exhibit strong interactions in chromosome conformation capture experiments, acute depletion of cohesin only mildly affects Sox2 transcription. Here we show that continuous loop extrusion, but not stalling of cohesin at CTCF sites is involved in the maintenance of the Sox2-SCR loop. While depletion of cohesin or CTCF has only a mild impact on Sox2 gene expression, stabilizing cohesin on the DNA by depleting the cohesin release factor WAPL results in a rapid decrease in expression. Furthermore, using genome editing we show that a weak enhancer located downstream from the Sox2 gene renders Sox2 expression insensitive to the loss of cohesin stalling at CTCF sites. Finally, through targeted and pleiotropic inhibition of the SCR we demonstrate that the Sox2-SCR loop is a multi-component system that depends on cohesin-mediated loop extrusion and enhancer-associated factors. Together, our findings highlight the intricate interplay between enhancer activity and loop extrusion in the establishment and maintenance of chromatin loops in the Sox2 locus.
2026-04-15 | GSE306297 | GEO