High-resolution CTCF footprinting reveals impact of chromatin state on cohesin extrusion

Corriene E. Sept, Y. Esther Tak, Viraat Goel, Mital S. Bhakta, Christian G. Cerda-Smith, Haley M. Hutchinson, Marco Blanchette, Christine E. Eyler, Sarah E. Johnstone, J. Keith Joung, Anders S. Hansen and Martin J. Aryee ()
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Corriene E. Sept: Harvard T.H. Chan School of Public Health
Y. Esther Tak: Massachusetts General Hospital
Viraat Goel: Broad Institute of MIT and Harvard
Mital S. Bhakta: Cantata Bio LLC
Christian G. Cerda-Smith: Duke University School of Medicine
Haley M. Hutchinson: Duke University School of Medicine
Marco Blanchette: Liftoff Biosolution
Christine E. Eyler: Duke University School of Medicine
Sarah E. Johnstone: Broad Institute of MIT and Harvard
J. Keith Joung: Massachusetts General Hospital
Anders S. Hansen: Broad Institute of MIT and Harvard
Martin J. Aryee: Harvard T.H. Chan School of Public Health

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Cohesin-mediated DNA loop extrusion enables gene regulation by distal enhancers through the establishment of chromosome structure and long-range enhancer-promoter interactions. The best characterized cohesin-related structures, such as topologically associating domains (TADs) anchored at convergent CTCF binding sites, represent static conformations. Consequently, loop extrusion dynamics remain poorly understood. To better characterize static and dynamically extruding chromatin loop structures, we use MNase-based 3D genome assays to simultaneously determine CTCF and cohesin localization as well as the 3D contacts they mediate. Here we present CTCF Analyzer (with) Multinomial Estimation (CAMEL), a tool that identifies CTCF footprints at near base-pair resolution in CTCF MNase HiChiP. We also use Region Capture Micro-C to identify a CTCF-adjacent footprint that is attributed to cohesin occupancy. We leverage this substantial advance in resolution to determine that the fully extruded (CTCF-CTCF loop) state is rare genome-wide with locus-specific variation from ~1–10%. We further investigate the impact of chromatin state on loop extrusion dynamics and find that active regulatory elements impede cohesin extrusion. These findings support a model of topological regulation whereby the transient, partially extruded state facilitates enhancer-promoter contacts that can regulate transcription.

Date: 2025
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DOI: 10.1038/s41467-025-57775-w

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