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Binding domain mutations provide insight into CTCF's relationship with chromatin and its contribution to gene regulation (RNA-seq, exit from pluripotency)

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE277846 | GEO | 2025/02/20

REPOSITORIES: GEO

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Binding domain mutations provide insight into CTCF's relationship with chromatin and its contribution to gene regulation (Hi-C)

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

Binding domain mutations provide insight into CTCF's relationship with chromatin and its contribution to gene regulation (Omni-ATAC)

2025-02-20 | GSE270626 | GEO

Systematic assessment of ISWI subunits reveals that NURF creates local accessibility for proper CTCF function

Project description:Catalytic activity of the ISWI family of remodelers is critical for nucleosomal organization and transcription factor binding, including the insulator protein CTCF. To define which subcomplex mediates these diverse functions we phenotyped a panel of isogenic mouse stem cell lines each lacking one of six ISWI accessory subunits. Individual deletions of either CERF, RSF1, ACF, WICH or NoRC subcomplexes only moderately affect the chromatin landscape, while removal of the NURF-specific subunit BPTF leads to drastic reduction in chromatin accessibility and Snf2h ATPase localization around CTCF sites. While this reduces distances to the adjacent nucleosomes it only modestly impacts CTCF binding itself. In absence of accessibility, the insulator function of CTCF is nevertheless impaired resulting in lower occupancy of cohesin and cohesin-loading factors, and reduced insulation at these sites, highlighting the need of NURF-mediated remodeling for open chromatin and proper CTCF function. Our comprehensive analysis reveals a specific role for NURF in mediating Snf2h localization and chromatin opening at bound CTCF sites showing that local accessibility is critical for cohesin binding and insulator function.

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X-chromosome dynamics revealed by the RNA interactome and chromosomal binding of CTCF

Project description:CTCF is a master regulator that plays a role in genome architecture and gene expression. A key aspect of CTCF’s mechanism involves bringing together distant genetic elements for intra- and inter-chromosomal interactions. Evidence from epigenetic processes, such as X-chromosome inactivation (XCI), suggests that CTCF may carry out its functions through interacting RNAs. Using genome-wide approaches to investigate the relationship between CTCF’s RNA interactome and its epigenomic landscape, here we report that CTCF interacts with thousands of transcripts in mouse embryonic stem cells (mESC), many in close proximity to CTCF’s genomic binding sites. Biochemical analysis demonstrates that CTCF is a high-affinity RNA binding protein that contacts RNA directly and specifically. In the XCI model, CTCF binds the active and inactive X-chromosomes allele-specifically. At the X-inactivation center, Tsix RNA binds CTCF and targets CTCF to a region associated with X-chromosome pairing. Our work implicates CTCF-RNA interactions in long-range chromosomal interactions in trans and adds a new layer of complexity to CTCF regulation. The genome-wide datasets reported here will provide a useful resource for further study of CTCF-mediated epigenomic regulation. CTCF RNA interactome was identified by UV-crosslinking and immunoprecipitation followed by high-throughput sequencing (CLIP-seq), and was compared to CTCF's epigenomic landscape as obtained by chromatin immunoprecipitation (ChIP-seq).

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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)

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.

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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

Comparative Hi-C reveals that CTCF underlies evolution of chromosomal domain architecture.

Project description:Topological domains are key architectural building blocks of chromosomes in complex genomes. Their functional importance and evolutionary dynamics are however not well defined. Here we performed comparative Hi-C in liver cells from four mammalian species, and characterized the conservation and divergence of chromosomal contact insulation and the resulting domain architectures within distantly related genomes. We show that the modular organization of chromosomes is robustly conserved in syntenic regions. This overall conservation is compatible with conservation of the binding landscape of the insulator protein CTCF. Specifically, conserved CTCF sites are co-localized with cohesin, enriched at strong topological domain borders and bind to DNA motifs with orientations that define the directionality of CTCF’s long-range interactions. Interestingly, CTCF binding sites which are divergent between species are strongly correlated with divergence of internal domain structure. This divergence is likely driven by local CTCF binding sequence changes, demonstrating how genome evolution can be linked directly with a continuous flux of local chromosome conformation changes. Conversely, we provide evidence that large-scale domains are harder to break and that they are reorganized during genome evolution as intact modules. Hi-C and 4C-seq experiments were conducted in primary liver cells obtained from mouse, rabbit, macaque and dog

2015-02-26 | E-GEOD-65126 | biostudies-arrayexpress

X-chromosome dynamics revealed by the RNA interactome and chromosomal binding of CTCF

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Long-range chromosome interactions mediated by cohesin shape circadian gene expression [RNA-Seq]

Project description:Mammalian circadian rhythm is established by the negative feedback loops consisting of a set of clock genes, which lead to the circadian expression of thousands of downstream genes. As genome-wide transcription is organized under the high-order chromosome structure, it is unclear how circadian gene expression is influenced by chromosome structure. In this study, we focus on the function of chromatin structure proteins cohesin as well as CTCF (CCCTC-binding factor) in circadian rhythm. We analyzed the interactome of a Bmal1-bound enhancer upstream of a clock gene, Nr1d1, by 4C-seq and observed that cohesin binding sites are enriched in the interactome. Integrating circadian transcriptome data and cistrome data, we found that cohesin-CTCF co-binding sites tend to insulate the phases of circadian oscillating genes while cohesin-non-CTCF sites facilitate the interaction between circadian enhancer and promoter. A coarse-grained model integrating the long-range effect of cohesin and CTCF markedly improved our mechanistic understanding of circadian gene expression. This model is subsequently supported by our RNA-seq data from cohesin knockout cells. Cohesin is required at least in part for driving the circadian gene expression by facilitating the enhancer-promoter looping. Taken together, our study provided a novel insight into the relationship between circadian transcriptome and the high-order chromosome structure. RNA-Seq in WT and Smc3-/- mouse embryonic fibroblast cells

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