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Promoter-proximal CTCF binding promotes distal enhancer-dependent gene activation II

ABSTRACT: The CCCTC-binding factor (CTCF) is widely regarded as a key player in chromosome organization in mammalian cells, yet direct assessment of its role in genome architecture and gene regulation has been difficult. Here, we use auxin-inducible degron techniques to acutely deplete CTCF to determine how loss of CTCF affect chromatin organization and gene expression. In mouse embryonic stem cells, depletion of CTCF results in rapid loss of chromatin loops anchored at CTCF-binding sites without major disruption to chromatin compartments and topological domains. In the absence of CTCF, many lineage-specific genes fail to express properly during differentiation to neural precursor cells, but transcriptional regulation of most genes is unaffected. Genes dependent on CTCF for induction are generally bound by the factor at promoters, which are connected to distal enhancers via CTCF-dependent chromatin loops. By contrast, CTCF-independent genes generally lack CTCF binding at the promoter and are generally closer to enhancers. These results refine our understanding of CTCF function in chromatin organization and gene regulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE146450 | GEO | 2020/03/06

REPOSITORIES: GEO

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Promoter-proximal CTCF binding promotes distal enhancer-dependent gene activation I

Project description:The CCCTC-binding factor (CTCF) is widely regarded as a key player in chromosome organization in mammalian cells, yet direct assessment of its role in genome architecture and gene regulation has been difficult. Here, we use auxin-inducible degron techniques to acutely deplete CTCF to determine how loss of CTCF affect chromatin organization and gene expression. In mouse embryonic stem cells, depletion of CTCF results in rapid loss of chromatin loops anchored at CTCF-binding sites without major disruption to chromatin compartments and topological domains. In the absence of CTCF, many lineage-specific genes fail to express properly during differentiation to neural precursor cells, but transcriptional regulation of most genes is unaffected. Genes dependent on CTCF for induction are generally bound by the factor at promoters, which are connected to distal enhancers via CTCF-dependent chromatin loops. By contrast, CTCF-independent genes generally lack CTCF binding at the promoter and are generally closer to enhancers. These results refine our understanding of CTCF function in chromatin organization and gene regulation.

2020-03-06 | GSE146449 | GEO

Promoter-proximal CTCF binding promotes distal enhancer-dependent gene activation IV

2020-03-06 | GSE146454 | GEO

Promoter-proximal CTCF binding promotes distal enhancer-dependent gene activation III

2020-03-06 | GSE146451 | GEO

CTCF binding polarity determines chromatin looping [4C]

Project description:CCCTC-binding factor (CTCF) is an architectural protein involved in the three-dimensional organization of chromatin. In this study, we systematically assayed the 3D genomic contact profiles of hundreds of CTCF binding sites in multiple tissues with high-resolution 4C-seq. We find both developmentally stable and dynamic chromatin loops. As recently reported, our data also suggest that chromatin loops preferentially form between CTCF binding sites oriented in a convergent manner. To directly test this, we used CRISPR-Cas9 genome editing to delete core CTCF binding sites in three loci, including the CTCF site in the Sox2 super-enhancer. In all instances, CTCF and cohesin recruitment were lost, and chromatin loops with distal CTCF sites were disrupted or destabilized. Re-insertion of oppositely oriented CTCF recognition sequences restored CTCF and cohesin recruitment, but did not re-establish chromatin loops. We conclude that CTCF binding polarity plays a functional role in the formation of higher order chromatin structure. 4C-seq was performed on a large number of viewpoints in E14 embryonic stem cells, neural precursor cells and primary fetal liver cells

2015-10-29 | E-GEOD-72539 | biostudies-arrayexpress

De novo mutations in the genome organizer CTCF cause Intellectual Disability (ChIP-Seq)

Project description:An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo missense mutation in the CTCF gene in individuals with intellectual disability, microcephaly and growth retardation. Furthermore, a patient with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. Transcriptome analyses in all three patients with point mutations revealed deregulation of genes involved in signal transduction and emphasized the role of CTCF in enhancer-driven expression of genes. Our findings indicate that haploinsufficiency of CTCF affects genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition. ChIP-seq analysis of CTCF genomic binding sites in lymphocytes of a control individual (no replicates).

2013-06-01 | E-GEOD-46832 | biostudies-arrayexpress

De novo mutations in the genome organizer CTCF cause Intellectual Disability (RNA-Seq)

Project description:An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo missense mutation in the CTCF gene in individuals with intellectual disability, microcephaly and growth retardation. Furthermore, a patient with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. Transcriptome analyses in all three patients with point mutations revealed deregulation of genes involved in signal transduction and emphasized the role of CTCF in enhancer-driven expression of genes. Our findings indicate that haploinsufficiency of CTCF affects genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition. Comparison of lymphocyte gene expression between 3 de novo CTCF mutation patients and 8 controls (4 technical replicates each, no biological replicates).

2013-06-01 | E-GEOD-46831 | biostudies-arrayexpress

CTCF binding polarity determines chromatin looping [4C]

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Genetic Evidence for Asymmetric Blocking of Higher-Order Chromatin Structure by CTCF/Cohesin

Project description:The architectural protein CTCF binds to mammalian insulators genome wide with directionality and recruits cohesin to mediate oriented long-distance chromatin loops. In many cases, CTCF-binding sites (CBSs) are associated with distal enhancers and target promoters. It is generally thought that CTCF binding results in spatial contacts between distal enhancers and target promoters leading to activation of specific promoters. However, how CTCF orchestrates higher-order chromatin organization to regulate gene expression is not fully understood. Here we used CRISPR DNA-fragment editing to investigate the roles of CTCF in chromatin organization of the clustered protocadherin (Pcdh) genes, which is an ideal model system with repertoires of CBSs in variable promoters and super-enhancers. We found that the CBSs at chromatin domain boundary and even single CBSs could determine the orientation of long-distance chromatin looping. In addition, deletion or inversion of large regions containing tandem CBS arrays in mice demonstrated asymmetric influences on chromatin looping between super-enhancers and target promoters. These genetic data have important implications on the assembly mechanisms of higher-order chromatin structures.

2019-09-15 | GSE135967 | GEO

Regulation of cohesin loop extrusion underlies changes in enhancer-promoter interactions during pancreatic cell differentiation (Hi-C)

Project description:Transcriptional reprogramming during cell fate determination involves precise targeting of enhancers to tissue-specific genes. Enhancer-promoter interactions are regulated by different types of 3D chromatin organization, including compartmental domains and CTCF loops. To understand the contribution of these different levels of chromatin organization in cell lineage commitment, we analyzed changes in 3D organization during the differentiation of human embryonic stem cells (hESCs) into pancreatic islet organoids. We find that major events in chromatin reorganization, including decompaction of transposon-enriched heterochromatin, breakdown of poised enhancer-promoter interaction networks, gain or loss of CTCF loops and establishment of novel enhancer-promoter contacts, occur either sequentially or simultaneously. Transcriptionally activated transposons released from unstable heterochromatin compartments recruit CTCF to form new loops. In contrast, when released from poised long-range interaction networks, enhancers and genes crucial for cell differentiation recruit tissue-specific transcription factors by either direct binding or indirect 3D contacts containing RNA Polymerase II. Activation of stage-specific genes correlates with gain of CTCF binding at anchors of extended CTCF loops, suggesting changes in loop extrusion capacity. In agreement with this, we find a global increase in cohesin loading leading to longer residency on extended CTCF loops encompassing tissue-specific genes. Our findings provide new insights into how distinct types of chromatin organization affect the reprogramming of gene expression patterns to regulate cell lineage commitment.

2023-09-19 | GSE210524 | GEO

Regulation of cohesin loop extrusion underlies changes in enhancer-promoter interactions during pancreatic cell differentiation (Hi-ChIP)

2023-09-19 | GSE210525 | GEO

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