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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE190358 | GEO | 2022/01/17

REPOSITORIES: GEO

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

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