ArticleEpigenetics & chromatin2026
Effects of topological domain disruption on transcriptional regulation are chromatin context dependent.
Article in Epigenetics & chromatin, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundThree-dimensional genome organization helps coordinate enhancer-promoter communication while insulating loci from inappropriate regulatory contacts. CTCF and cohesin contribute to this organization by forming topologically associating domains. However, how boundary elements at individual loci influence transcription remains context dependent.
resultsWe investigated the conserved topological organization of the mammalian NOTCH1 locus. Across human cell types, NOTCH1 resides within a defined topologically associated domain with CTCF/cohesin occupancy at both 5' and 3' boundaries. In human K562 cells, CRISPR-Cas9 deletion of boundary CTCF sites increased transcription of NOTCH1 and the intradomain non-coding transcripts NALT1 and LINC01451. Boundary perturbations impaired proliferation and clonogenic growth. Chromatin conformation profiling revealed defects in domain insulation and a redistribution of regulatory contacts between NOTCH1 promoter and enhancers within the domain. Cross-species analyses showed that domain architecture is conserved in mouse, yet transcriptional and phenotypic effects associated to domain boundary disruption were cell-type specific and correlated with differential chromatin contexts.
conclusionsCTCF-dependent boundary integrity at the NOTCH1 locus tunes transcriptional output and cellular phenotypes in a chromatin context-dependent manner, supporting a model in which conserved 3D architecture constrains regulatory communication but yields distinct outcomes across cellular states.
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