{"doi":"10.1101/2025.07.29.667515","title":"Histone Acetylation Differentially Modulates CTCF-CTCF Loops and Intra-TAD Interactions","abstract":"The cohesin complex structures the interphase genome by extruding loops and organizing topologically associating domains (TADs). While cohesin engages chromatin in context-dependent modes, the regulatory influence of chromatin state on these interactions remains unclear. Here, we show that histone hyperacetylation, induced by the histone deacetylase inhibitor trichostatin A (TSA), preferentially disrupts short-range interactions within TADs but spares CTCF-anchored loops, despite reduced cohesin occupancy at these sites. These findings point to two functionally distinct cohesin populations: a TSA-sensitive pool within TADs, likely representing extruding, non-topologically bound cohesin, and a TSA-resistant population at CTCF-CTCF anchors that maintains loops through topological entrapment. Using a semi-in vitro system with TEV-cleavable RAD21, we show that TSA-resistant cohesin at CTCF sites becomes TSA-sensitive after proteolytic cleavage that opens the cohesin ring, showing that it is the topological engagement with DNA that makes cohesin, and CTCF-CTCF loops, TSA-resistant. Notably, we also detect TSA-sensitive cohesin at CTCF sites, suggesting the presence of transient, non-encircling cohesin that either precedes conversion to the stable form or is halted by pre-existing encircling cohesin. Together, our results suggest that cohesin exists in distinct biochemical states: an extruding form found within TADs and at CTCF sites, that is sensitive to hyperacetylation, and a topologically bound form specifically at CTCF-CTCF loops that is insensitive. The former may allow dynamic changes in chromatin loops, while latter ensures robustness of CTCF-anchored loops in response to chromatin state changes.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":556614,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1455836,"name":"Y. Fu","orcid":"0000-0002-2854-5622","position":1,"is_corresponding":false},{"id":1456296,"name":"Kathleen L Schiela","orcid":null,"position":2,"is_corresponding":false},{"id":1455837,"name":"Madison Dautle","orcid":"0009-0004-7927-3825","position":3,"is_corresponding":false},{"id":1455838,"name":"Ryan Williams","orcid":"0000-0002-3185-3909","position":4,"is_corresponding":false},{"id":1456297,"name":"Hannah M Wilson","orcid":null,"position":5,"is_corresponding":false},{"id":993200,"name":"Chloe Azadegan","orcid":"0000-0002-1266-1637","position":6,"is_corresponding":false},{"id":667579,"name":"Johnathan R. Whetstine","orcid":"0000-0003-0555-4283","position":7,"is_corresponding":false},{"id":11679,"name":"Job Dekker","orcid":"0000-0001-5631-0698","position":8,"is_corresponding":false},{"id":493931,"name":"Yu Liu","orcid":"0000-0001-8359-6732","position":9,"is_corresponding":false},{"id":284875,"name":"Rebecca G. Smith","orcid":"0000-0001-9264-1056","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:55:08.896385Z","pmid":"40766525","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}