Brain and cancer associated binding domain mutations provide insight into CTCF’s relationship with chromatin and its ability to act as a chromatin organizer (chip-seq)
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PROVIDER: PRJNA1127577 | ENA |
REPOSITORIES: ENA
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Project description:Although only a fraction of CTCF motifs are bound in any cell type, and approximately half of the occupied sites overlap cohesin, the mechanisms underlying cell-type specific attachment and ability to function as a chromatin organizer remain unknown. To investigate the relationship between CTCF and chromatin we applied a combination of imaging, structural and molecular approaches, using a series of brain and cancer associated CTCF mutations that act as CTCF perturbations. We demonstrate that binding and the functional impact of WT and mutant CTCF depend not only on the unique properties of each protein, but also on the genomic context of bound sites. Our studies also highlight the reciprocal relationship between CTCF and chromatin, demonstrating that the unique binding properties of WT and mutant proteins have a distinct impact on accessibility, TF binding, cohesin overlap, chromatin interactivity and gene expression programs, providing insight into their cancer and brain related effects.
2025-02-20 | GSE270620 | GEO
Project description:Although only a fraction of CTCF motifs are bound in any cell type, and approximately half of the occupied sites overlap cohesin, the mechanisms underlying cell-type specific attachment and ability to function as a chromatin organizer remain unknown. To investigate the relationship between CTCF and chromatin we applied a combination of imaging, structural and molecular approaches, using a series of brain and cancer associated CTCF mutations that act as CTCF perturbations. We demonstrate that binding and the functional impact of WT and mutant CTCF depend not only on the unique properties of each protein, but also on the genomic context of bound sites. Our studies also highlight the reciprocal relationship between CTCF and chromatin, demonstrating that the unique binding properties of WT and mutant proteins have a distinct impact on accessibility, TF binding, cohesin overlap, chromatin interactivity and gene expression programs, providing insight into their cancer and brain related effects.
2025-02-20 | GSE270619 | GEO
Project description:Brain and cancer associated binding domain mutations provide insight into CTCF’s relationship with chromatin and its ability to act as a chromatin organizer (RNA-seq)
| PRJNA1127578 | ENA
Project description:Here we used a series of CTCF mutations to explore CTCF’s relationship with chromatin and its contribution to gene regulation. CTCF’s impact depends on the genomic context of bound sites and the unique binding properties of WT and mutant CTCF proteins. Specifically, CTCF’s signal strength is linked to changes in accessibility, and the ability to block cohesin is linked to its binding stability. Multivariate modelling reveals that both CTCF and accessibility contribute independently to cohesin binding and insulation, however CTCF signal strength has a stronger effect. CTCF and chromatin have a bidirectional relationship such that at CTCF sites, accessibility is reduced in a cohesin-dependent, mutant specific fashion. In addition, each mutant alters TF binding and accessibility in an indirect manner, changes which impart the most influence on rewiring transcriptional networks and the cell’s ability to differentiate. Collectively, the mutant perturbations provide a rich resource for determining CTCF’s site-specific effects.
2025-02-20 | GSE270627 | GEO
Project description:Here we used a series of CTCF mutations to explore CTCF’s relationship with chromatin and its contribution to gene regulation. CTCF’s impact depends on the genomic context of bound sites and the unique binding properties of WT and mutant CTCF proteins. Specifically, CTCF’s signal strength is linked to changes in accessibility, and the ability to block cohesin is linked to its binding stability. Multivariate modelling reveals that both CTCF and accessibility contribute independently to cohesin binding and insulation, however CTCF signal strength has a stronger effect. CTCF and chromatin have a bidirectional relationship such that at CTCF sites, accessibility is reduced in a cohesin-dependent, mutant specific fashion. In addition, each mutant alters TF binding and accessibility in an indirect manner, changes which impart the most influence on rewiring transcriptional networks and the cell’s ability to differentiate. Collectively, the mutant perturbations provide a rich resource for determining CTCF’s site-specific effects.
2025-02-20 | GSE270626 | GEO
Project description:Here we used a series of CTCF mutations to explore CTCF’s relationship with chromatin and its contribution to gene regulation. CTCF’s impact depends on the genomic context of bound sites and the unique binding properties of WT and mutant CTCF proteins. Specifically, CTCF’s signal strength is linked to changes in accessibility, and the ability to block cohesin is linked to its binding stability. Multivariate modelling reveals that both CTCF and accessibility contribute independently to cohesin binding and insulation, however CTCF signal strength has a stronger effect. CTCF and chromatin have a bidirectional relationship such that at CTCF sites, accessibility is reduced in a cohesin-dependent, mutant specific fashion. In addition, each mutant alters TF binding and accessibility in an indirect manner, changes which impart the most influence on rewiring transcriptional networks and the cell’s ability to differentiate. Collectively, the mutant perturbations provide a rich resource for determining CTCF’s site-specific effects.
2025-02-20 | GSE277846 | GEO
Project description:CTCF, a highly studied transcription factor, is essential for chromatin interaction maintenance. Several independent studies have reported that CTCF interacts with RNAs in vitro and in cells. Yet continuous debates about the authenticity of the RNA-binding affinity of CTCF and its biological role remain in large part due to limited research techniques available, such as CLIP-seq. Here, we investigated the role RNA plays on CTCF’s transcription factor function through its chromatin occupancy. To systematically investigate whether RNAs affect CTCF’s ability to bind DNA, we perturbed CTCF-RNA interactions by three independent approaches and examined CTCF genome occupancy by ChIP-seq. Although RnaseA A and Triptolide treatment each affected a certain number of CTCF-binding peaks, few peaks overlapped between treatment groups indicating the effect of RNA in regulating CTCF’s DNA binding affinity was modest and variable between loci. In addition, limited transcriptional or chromatin accessibility changes were observed between cells expressing wild-type CTCF or CTCF lacking the RNA binding region. Our data provide a complementary approach and in silico evidence to reconsider the significance of RNA affecting CTCF’s DNA-binding affinity in a global manner.
2024-11-11 | GSE281633 | GEO
Project description:Studies of the Xenopus organizer have laid the foundation for our understanding of the conserved signaling pathways that pattern vertebrate embryos during gastrulation. Here, we use this wealth of knowledge as leverage in the design and analysis of a genomic visualization of organizer-related gene transcription. Using ectopic expression of the two major activities of the organizer, BMP and Wnt inhibition, as well as endogenous tissues, we generate a focused set of samples that represent different aspects of organizer signaling. The genomic expression values of each sample are then measured with oligonucleotide arrays. From this data, genes regulated by organizer signaling are selected and then clustered by their patterns of regulation. A new GO biological process annotation of the Xenopus genome allows us to rapidly identify clusters that are highly enriched for known gastrula patterning genes. Within these clusters, we can predict the expression patterns of unknown genes with remarkable accuracy, leading to the discovery of new organizer-related gastrula stage expression patterns for 19 genes. Moreover, the patterns of gene response observed within these clusters allow us to parse apart the contributions of BMP and Wnt inhibition in organizer function. We find that the majority of gastrula patterning genes respond transcriptionally to these activities according to only a few stereotyped patterns, allowing us to describe suites of genes that are likely to share similar regulatory mechanisms. These suites of genes demonstrate a mechanism where BMP inhibition initiates the organizer program before gastrulation, and Wnt inhibition maintains and drives the organizer program during gastrulation. Keywords: development, organizer, noggin, dkk-1, xenopus, gastrulation
2006-06-30 | GSE3368 | GEO
Project description:Recapitulation of development in vitro relies primarily on treatment of progenitor cells with media-borne morphogens, without the complex spatial instructions normally presented by native developmental niches. Here we build simple spatially asymmetric developmental niches by engineering synthetic organizer cells that self-assemble around stem cells and provide spatially-defined morphogenic instructions. Using a toolkit of natural and engineered adhesion molecules we harness differential adhesion to program the formation of specific organizer cell geometries around the stem cells, allowing the generation of morphogen gradients with tunable position, amplitude, and signal types. Synthetic niches presenting the antagonistic morphogens WNT3A and DKK1 were used to guide development of pluripotent stem cells. These synthetic organizers generated distinct morphological outcomes, including formation of a beating heart-like chamber and embryoids containing a complement of diverse cell lineages derived from mesoderm, endoderm and ectoderm. The resulting morphologies were reproducible in high-throughput format. Spatially programmable synthetic organizer cells, which integrate the principles of differential adhesion and positional information, thus provide a systematic approach to guide, recapitulate, and modify development in a controlled fashion.
2024-12-09 | GSE244033 | GEO