{"doi":"10.1101/2025.11.18.685822","title":"Widespread low-affinity motifs enhance chromatin accessibility and regulatory potential in mESCs","abstract":"Low-affinity transcription factor (TF) motifs are an important element of the cis-regulatory code, yet they are notoriously difficult to map and mechanistically incompletely understood, limiting our ability to interpret non-coding variation in development, evolution, and disease. Here we investigate their role in pioneering and leverage sequence-to-profile models of chromatin accessibility in mouse embryonic stem cells to reliably map and interpret low-affinity motifs across the genome. We find that low-affinity motifs have outsized effects by cooperating with nearby motifs through intra-nucleosomal soft syntax. By modeling nucleosome-mediated cooperativity with a kinetic model, we discover and validate that pioneer cooperativity makes a motif operate at higher pioneering ranges across changing TF concentrations, thereby raising the regulatory potential. These results show that low-affinity motifs can be accurately mapped, shape the properties of developmental enhancers and likely play a widespread role in fine-tuning enhancers during evolution.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":559538,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9513,"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":986379,"name":"Kaelan Brennan","orcid":"0000-0002-4237-4874","position":1,"is_corresponding":false},{"id":615217,"name":"Khyati Dalal","orcid":"0000-0002-1867-5079","position":2,"is_corresponding":false},{"id":615216,"name":"Sabrina Krueger","orcid":"0000-0001-6581-1590","position":3,"is_corresponding":false},{"id":1460799,"name":"Haining Jiang","orcid":"0000-0002-0989-5301","position":4,"is_corresponding":false},{"id":560548,"name":"Rosa Martinez-Corral","orcid":"0000-0003-3600-3601","position":5,"is_corresponding":false},{"id":23592,"name":"Julia Zeitlinger","orcid":"0000-0002-5172-3335","position":6,"is_corresponding":false},{"id":615215,"name":"Melanie Weilert","orcid":"0000-0001-8683-4580","position":0,"is_corresponding":true}],"reference_count":120,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:34.849815Z","pmid":"41332771","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":[]}