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CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE153403 | GEO | 2020/07/06

REPOSITORIES: GEO

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CTCF mediates dosage- and sequence-context-dependent transcriptional insulation by forming local chromatin domains.

Project description:Insulators play a critical role in spatiotemporal gene regulation in animals. The evolutionarily conserved CCCTC-binding factor (CTCF) is required for insulator function in mammals, but not all of its binding sites act as insulators. Here we explore the sequence requirements of CTCF-mediated transcriptional insulation using a sensitive insulator reporter in mouse embryonic stem cells. We find that insulation potency depends on the number of CTCF-binding sites in tandem. Furthermore, CTCF-mediated insulation is dependent on upstream flanking sequences at its binding sites. CTCF-binding sites at topologically associating domain boundaries are more likely to function as insulators than those outside topologically associating domain boundaries, independently of binding strength. We demonstrate that insulators form local chromatin domain boundaries and weaken enhancer-promoter contacts. Taken together, our results provide genetic, molecular and structural evidence connecting chromatin topology to the action of insulators in the mammalian genome.

| S-EPMC8853952 | biostudies-literature

CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains [ChIP-seq]

Project description:Insulators play a critical role in spatiotemporal gene expression in metazoans by separating active and repressive chromatin domains and preventing inappropriate enhancer-promoter contacts. The evolutionarily conserved CCCTC-binding factor (CTCF) is required for insulator function in mammals, but not all of its binding sites act as insulators. Here, we explore the sequence requirements of CTCF-mediated transcriptional insulation with the use of a sensitive insulator reporter assay in mouse embryonic stem cells. We find that potent insulation is provided by multiple CTCF binding sites. Furthermore, CTCF-mediated insulation is dependent on DNA sequences adjacent to its core binding motifs, and CTCF binding sites from topologically associating domains (TAD) boundaries are more likely to function as insulators than those outside TAD boundaries independent of binding strength. Using chromosomal conformation capture assays and high resolution chromatin imaging techniques, we demonstrate that insulators reduce enhancer-promoter contacts by forming local chromatin domains. Taken together, our results provide strong genetic, molecular and imaging evidence connecting chromatin topology to action of insulators in the mammalian genome.

2020-07-06 | GSE153400 | GEO

CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains [RNA-seq]

2020-11-25 | GSE162101 | GEO

CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains [Hi-C and PLAC-seq]

2020-07-06 | GSE153402 | GEO

CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains

Project description:CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains

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CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains [RNA-seq]

Project description:CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains [RNA-seq]

| PRJNA680582 | ENA

CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains [ChIP-seq]

Project description:CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains [ChIP-seq]

| PRJNA642298 | ENA

CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains [Hi-C and PLAC-seq]

Project description:CTCF Mediates Dosage and Sequence-context-dependent Transcriptional Insulation through Formation of Local Chromatin Domains [Hi-C and PLAC-seq]

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Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization.

Project description:The molecular mechanisms underlying folding of mammalian chromosomes remain poorly understood. The transcription factor CTCF is a candidate regulator of chromosomal structure. Using the auxin-inducible degron system in mouse embryonic stem cells, we show that CTCF is absolutely and dose-dependently required for looping between CTCF target sites and insulation of topologically associating domains (TADs). Restoring CTCF reinstates proper architecture on altered chromosomes, indicating a powerful instructive function for CTCF in chromatin folding. CTCF remains essential for TAD organization in non-dividing cells. Surprisingly, active and inactive genome compartments remain properly segregated upon CTCF depletion, revealing that compartmentalization of mammalian chromosomes emerges independently of proper insulation of TADs. Furthermore, our data support that CTCF mediates transcriptional insulator function through enhancer blocking but not as a direct barrier to heterochromatin spreading. Beyond defining the functions of CTCF in chromosome folding, these results provide new fundamental insights into the rules governing mammalian genome organization.

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Cooperative insulation of regulatory domains by CTCF-dependent physical insulation and promoter competition

Project description: Not available

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