Cross-platform Hi-C meta-analysis identifies functional insulators that actively block enhancer-promoter interactions
Year: 2026
Type: article
Abstract: The function of topologically associating domain (TAD) boundaries as transcriptional insulators remains a fundamental controversy in genome biology. Here, we demonstrate that bona fide Functional Insulators (FINs) should be defined dynamically by their capability to block architectural rewiring. Leveraging DeepLoop to enable robust cross-platform Hi-C analysis, we performed a meta-analysis of nine high-resolution 3D genomic datasets following acute CTCF or cohesin depletion, mapping FINs genome-wide. We show that CTCF loss triggers the reproducible formation of new enhancer-promoter loops at only a few hundred specific loci. These loops are cohesin-dependent, enriched at G-rich cis-regulatory elements, and directly drive recurrent, early-response gene activation. Multiplexed CTCF-displacement assays functionally confirmed the causal role of FINs in these localized rewiring events. Crucially, FINs reside within active euchromatin, infrequently coincide with traditional TAD boundaries, and are sensitive to WAPL depletion. Our results reveal that the genome's functional insulation is mediated by these discrete, dynamically active sites rather than static TAD boundaries.
Source: Nature Communications
Authors: Jian Cui, Wanying Xu, Xiuyuan Lang, Shanshan Zhang, Leina Lu, Xiaoxiao Liu, Yan Li, Fulai Jin
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: University of Miami, Case Western Reserve University, National Institutes of Health, National Institute on Aging, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: G1099034210, G1244842289, G3613899374, G445699482, G4692453154, G498672744, G8209644491, G9000068178, G9000219505, Robust mapping of chromatin loops from sparse or single cell Hi-C data with DeepLoop, Mechanisms of PIK3CA helical domain mutations driving colorectal tumorigenesis, STAG2 mutations and 3D genome organization in glioblastoma multiforme, Targeting Oncostatin M-Receptor to Suppress Metastasis and Therapy Failure
OpenAlex ID: W7169030941