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Functional maps of a genomic locus reveal confinement of an enhancer by its target gene [Tagmentation]

ABSTRACT: Genes are often activated by enhancers located at large genomic distances. The importance of this positioning is poorly understood. Here, by relocating different promoter-reporter constructs into >1,000 alternative positions within a single locus, we dissected the positional relationship between the mouse Sox2 gene and its distal enhancer. This revealed an intricate, sharply confined activation landscape, in which the native Sox2 gene occupies an optimal position for its activation. Deletion of the gene relaxes this confinement and broadly increases reporter activity. Surprisingly, this confining effect of the Sox2 gene on reporter activity is partially conferred by its ~1 kb coding region. Our local relocation approach provides high-resolution functional maps of a genomic locus and reveals that a gene can strongly constrain its enhancer’s realm of influence.

ORGANISM(S): Mus musculus

PROVIDER: GSE274893 | GEO | 2024/08/19

REPOSITORIES: GEO

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Functional maps of a genomic locus reveal confinement of an enhancer by its target gene [ChIP-seq]

Project description:Genes are often activated by enhancers located at large genomic distances. The importance of this positioning is poorly understood. Here, by relocating different promoter-reporter constructs into >1,000 alternative positions within a single locus, we dissected the positional relationship between the mouse Sox2 gene and its distal enhancer. This revealed an intricate, sharply confined activation landscape, in which the native Sox2 gene occupies an optimal position for its activation. Deletion of the gene relaxes this confinement and broadly increases reporter activity. Surprisingly, this confining effect of the Sox2 gene on reporter activity is partially conferred by its ~1 kb coding region. Our local relocation approach provides high-resolution functional maps of a genomic locus and reveals that a gene can strongly constrain its enhancer’s realm of influence.

2024-08-19 | GSE274894 | GEO

ChIP-chip of MCF7 Sox2 regulatory region 2 transcription activity reporter unresponsive and reporter responsive breast cancer cells

Project description:We found that MCF7 and ZR751 Sox2-expressing breast cancer cell lines comprise of cells with heterogeneous Sox2 transcription activity reporter response. A small subset of Sox2 reporter responsive cells are more tumourigenic than the bulk Sox2 reporter unresponsive cells. We questioned whether Sox2 exhibit differential gene promoter occupancies in the two cell subsets to govern differential gene expression patterns. Sox2 ChIP in reporter unresponsive (RU) and reporter responsive (RR) cells (duplicate samples) were compared. IgG ChIP in RU and RR cells served as the negative controls.

2014-09-25 | E-GEOD-61703 | biostudies-arrayexpress

ChIP-chip of MCF7 Sox2 regulatory region 2 transcription activity reporter unresponsive and reporter responsive breast cancer cells

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Pioneer activity distinguishes activating from non-activating SOX2 binding sites

Project description:Genome-wide transcriptional activity involves the binding of many transcription factors to thousands of sites in the genome. Determining which sites are directly driving transcription remains a challenge. Here we use acute protein depletion of the pioneer transcription factor SOX2 to establish its functionality in maintaining chromatin accessibility. We show that thousands of accessible sites are lost within an hour of protein depletion, indicating rapid turnover of these sites in the absence of pioneer factors. To understand the relationship with transcription we performed nascent transcription analysis and found that open chromatin sites that are maintained by SOX2 are highly predictive of gene expression, in contrast to all other SOX2 binding sites. We use CRISPR-Cas9 genome editing in the Klf2 locus to functionally validate a predicted regulatory element. We conclude that the regulatory activity of SOX2 is exerted largely at sites where it maintains accessibility and that other binding sites are largely dispensable for gene regulation.

2023-10-24 | PXD043672 | Pride

Genomic context sensitizes regulatory elements to genetic disruption [DNAse-seq]

Project description:Enhancer function is frequently investigated piecemeal using truncated reporter assays or single deletion analysis, thus it remains unclear to what extent their function is influenced by surrounding genomic context. Using our Big-IN technology for targeted integration of large DNAs, we analyzed the regulatory architecture of the Igf2/H19 locus, a paradigmatic model of enhancer selectivity. We assembled payloads containing a 157-kb functional Igf2/H19 locus and engineered mutations to genetically direct CTCF occupancy at the imprinting control region (ICR) that switches the target gene of the H19 enhancer cluster. Contrasting the activity of payloads delivered to the endogenous locus or to a safe harbor locus (Hprt) revealed that the functional elements comprising the Igf2/H19 locus are highly sensitive to their native context. Exchanging components of the Igf2/H19 locus with the well-studied Sox2 locus showed that the H19 enhancer cluster in particular functioned poorly out of context, and required its native surroundings to activate Sox2 expression. Conversely, the Sox2 locus control region (LCR) could activate both Igf2 and H19 outside its native context, but its activity was only partially modulated by CTCF occupancy at the ICR. Analysis of regulatory DNA actuation across different cell types revealed that, while the H19 enhancers are tightly coordinated within their native locus, the Sox2 LCR acts more independently. We show that these enhancer clusters typify broader classes of loci genome-wide. Our results show that unexpected dependencies may influence even the most studied functional elements, and our synthetic regulatory genomics approach permits large-scale manipulation of complete loci to investigate how locus architecture relates to function.

2024-03-13 | GSE241707 | GEO

Genomic context sensitizes regulatory elements to genetic disruption [DNA]

2024-03-13 | GSE241706 | GEO

Genomic context sensitizes regulatory elements to genetic disruption [CUT&RUN]

2024-03-13 | GSE241705 | GEO

Project description:A small number of transcription factors, including Oct-3/4 and Sox2, constitute the transcriptional network that maintains pluripotency in embryonic stem (ES) cells. Previous reports suggested that some of these factors form a complex that binds the Oct-Sox element, a composite sequence consisting of closely juxtaposed Oct-3/4-binding and Sox2-binding sites. However, little is known regarding the components of the complex. In this study, we show that Sall4, a member of the Spalt-like family of proteins, directly interacts with Sox2 and Oct-3/4. Sall4 in combination with Sox2 or Oct-3/4 simultaneously occupies the Oct-Sox elements in mouse ES cells. Sall4 knockdown led to differentiation of ES cells. Overexpression of Sall4 in ES cells increased reporter activities in a luciferase assay when the Pou5f1- or Nanog-derived Oct-Sox element was included in the reporter. Microarray analyses revealed that Sall4 and Sox2 bound to the same genes in ES cells significantly more frequently than expected from random coincidence. These factors appeared to bind the promoter regions of a subset of the Sall4- and Sox2-double-positive genes in precisely similar distribution patterns along the promoter regions, suggesting that Sall4 and Sox2 associate with such Sall4/Sox2-overlapping genes as a complex. Importantly, gene ontology analyses indicated that the Sall4/Sox2-overlapping gene set is enriched for genes involved in maintaining pluripotency. Sall4/Sox2/Oct-3/4-triple-positive genes identified by referring to a previous study identifying Oct-3/4-bound genes in ES cells were further enriched for pluripotency genes than Sall4/Sox2-double-positive genes. These results demonstrate that Sall4 contributes to the transcriptional network operating in pluripotent cells, together with Oct-3/4 and Sox2. ChIP-on-chip experiments using anti-Sall4 or anti-Sox2 antibody were performed.

2012-12-28 | E-GEOD-40072 | biostudies-arrayexpress

4C on Sox2 Locus with tetO/cuO Modifications

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2019-05-16 | GSE127901 | GEO

Identification the Expression of Sox2 in Colorectal Cancer Tissues

Project description:Sox2 has been studied in several types of human solid tumors. The investigators found that Sox2 had higher expression level in colorectal cancer and metastatic tissues than normal tissues. So the investigators assumed that whether Sox2 plays an important role in the progression and migration of colon cancer.

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