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High affinity enhancer promoter interactions can bypass strong CTCF/cohesin-mediated insulation contributing to phenotypic robustness

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

ORGANISM(S): Mus musculus

PROVIDER: GSE190359 | GEO | 2021/12/30

REPOSITORIES: GEO

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High affinity enhancer promoter interactions can bypass strong CTCF/cohesin-mediated insulation contributing to phenotypic robustness [ChIP-seq]

Project description:Transcriptional control by enhancers located at large genomic distances from their targets is a common and integral feature of gene regulation. To understand how tissue specific enhancer-promoter interactions arise and to assess their resilience to perturbation of chromatin architecture, we generated an allelic series of mouse mutants carrying modifications to the structure of the Sox2 locus. We show that in pre-implantation epiblast cells and in neuronal lineages, CTCF-mediated loops are neither required for the interaction of Sox2 with its long-distance enhancers nor for its expression. Sox2-enhancer interactions in these cells were also robust to the introduction of CTCF/cohesin-mediated loops of varying degrees of insulation. These loops led to reduced interactions and Sox2 expression but did not cause their full disruption and were compatible with implantation and neurogenesis. In contrast, Sox2 expression in the anterior foregut was highly susceptible to perturbation of local chromatin structure with mutant embryos failing to separate trachea from esophagus and dying perinatally. Thus, in addition to being locus-specific, the functional impact of nuclear organization on cell fate-decisions is also highly dependent on biological context. Our work highlights the need of studying nuclear organization mechanisms in vivo and suggests that high-affinity enhancer-promoter interactions can provide robustness to structural perturbations to ensure faithful phenotypic outcomes.

2022-01-17 | GSE190358 | GEO

High affinity enhancer promoter interactions can bypass strong CTCF/cohesin-mediated insulation contributing to phenotypic robustness [Capture Hi-C]

2021-12-30 | GSE190357 | GEO

High affinity enhancer promoter interactions can bypass strong CTCF/cohesin-mediated insulation contributing to phenotypic robustness

Project description:High affinity enhancer promoter interactions can bypass strong CTCF/cohesin-mediated insulation contributing to phenotypic robustness

| PRJNA786856 | ENA

High affinity enhancer promoter interactions can bypass strong CTCF/cohesin-mediated insulation contributing to phenotypic robustness [ChIP-seq]

Project description:High affinity enhancer promoter interactions can bypass strong CTCF/cohesin-mediated insulation contributing to phenotypic robustness [ChIP-seq]

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High affinity enhancer promoter interactions can bypass strong CTCF/cohesin-mediated insulation contributing to phenotypic robustness [Capture Hi-C]

Project description:High affinity enhancer promoter interactions can bypass strong CTCF/cohesin-mediated insulation contributing to phenotypic robustness [Capture Hi-C]

| PRJNA786863 | ENA

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

Project description: Not available

| S-EPMC11344162 | biostudies-literature

CTCF/cohesin-mediated DNA looping is required for protocadherin ? promoter choice.

Project description:The closely linked human protocadherin (Pcdh) ?, ?, and ? gene clusters encode 53 distinct protein isoforms, which are expressed in a combinatorial manner to generate enormous diversity on the surface of individual neurons. This diversity is a consequence of stochastic promoter choice and alternative pre-mRNA processing. Here, we show that Pcdh? promoter choice is achieved by DNA looping between two downstream transcriptional enhancers and individual promoters driving the expression of alternate Pcdh? isoforms. In addition, we show that this DNA looping requires specific binding of the CTCF/cohesin complex to two symmetrically aligned binding sites in both the transcriptionally active promoters and in one of the enhancers. These findings have important implications regarding enhancer/promoter interactions in the generation of complex Pcdh cell surface codes for the establishment of neuronal identity and self-avoidance in individual neurons.

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CTCF physically links cohesin to chromatin.

Project description:Cohesin is required to prevent premature dissociation of sister chromatids after DNA replication. Although its role in chromatid cohesion is well established, the functional significance of cohesin's association with interphase chromatin is not clear. Using a quantitative proteomics approach, we show that the STAG1 (Scc3/SA1) subunit of cohesin interacts with the CCTC-binding factor CTCF bound to the c-myc insulator element. Both allele-specific binding of CTCF and Scc3/SA1 at the imprinted IGF2/H19 gene locus and our analyses of human DM1 alleles containing base substitutions at CTCF-binding motifs indicate that cohesin recruitment to chromosomal sites depends on the presence of CTCF. A large-scale genomic survey using ChIP-Chip demonstrates that Scc3/SA1 binding strongly correlates with the CTCF-binding site distribution in chromosomal arms. However, some chromosomal sites interact exclusively with CTCF, whereas others interact with Scc3/SA1 only. Furthermore, immunofluorescence microscopy and ChIP-Chip experiments demonstrate that CTCF associates with both centromeres and chromosomal arms during metaphase. These results link cohesin to gene regulatory functions and suggest an essential role for CTCF during sister chromatid cohesion. These results have implications for the functional role of cohesin subunits in the pathogenesis of Cornelia de Lange syndrome and Roberts syndromes.

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CTCF, Cohesin, and Chromatin in Human Cancer.

Project description:It is becoming increasingly clear that eukaryotic genomes are subjected to higher-order chromatin organization by the CCCTC-binding factor/cohesin complex. Their dynamic interactions in three dimensions within the nucleus regulate gene transcription by changing the chromatin architecture. Such spatial genomic organization is functionally important for the spatial disposition of chromosomes to control cell fate during development and differentiation. Thus, the dysregulation of proper long-range chromatin interactions may influence the development of tumorigenesis and cancer progression.

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Combined CRISPRi and proteomics screening reveal a cohesin-CTCF-bound allele contributing to increased expression of RUVBL1 and prostate cancer progression.

Project description:Genome-wide association studies along with expression quantitative trait locus (eQTL) mapping have identified hundreds of single-nucleotide polymorphisms (SNPs) and their target genes in prostate cancer (PCa), yet functional characterization of these risk loci remains challenging. To screen for potential regulatory SNPs, we designed a CRISPRi library containing 9,133 guide RNAs (gRNAs) to cover 2,166 candidate SNP loci implicated in PCa and identified 117 SNPs that could regulate 90 genes for PCa cell growth advantage. Among these, rs60464856 was covered by multiple gRNAs significantly depleted in screening (FDR < 0.05). Pooled SNP association analysis in the PRACTICAL and FinnGen cohorts showed significantly higher PCa risk for the rs60464856 G allele (p value = 1.2 × 10-16 and 3.2 × 10-7, respectively). Subsequent eQTL analysis revealed that the G allele is associated with increased RUVBL1 expression in multiple datasets. Further CRISPRi and xCas9 base editing confirmed that the rs60464856 G allele leads to elevated RUVBL1 expression. Furthermore, SILAC-based proteomic analysis demonstrated allelic binding of cohesin subunits at the rs60464856 region, where the HiC dataset showed consistent chromatin interactions in prostate cell lines. RUVBL1 depletion inhibited PCa cell proliferation and tumor growth in a xenograft mouse model. Gene-set enrichment analysis suggested an association of RUVBL1 expression with cell-cycle-related pathways. Increased expression of RUVBL1 and activation of cell-cycle pathways were correlated with poor PCa survival in TCGA datasets. Our CRISPRi screening prioritized about one hundred regulatory SNPs essential for prostate cell proliferation. In combination with proteomics and functional studies, we characterized the mechanistic role of rs60464856 and RUVBL1 in PCa progression.

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