{"doi":"10.1093/nar/gkaa012","title":"Dynamic changes in cis-regulatory occupancy by Six1 and its cooperative interactions with distinct cofactors drive lineage-specific gene expression programs during progressive differentiation of the auditory sensory epithelium","abstract":"The transcription factor Six1 is essential for induction of sensory cell fate and formation of auditory sensory epithelium, but how it activates gene expression programs to generate distinct cell-types remains unknown. Here, we perform genome-wide characterization of Six1 binding at different stages of auditory sensory epithelium development and find that Six1-binding to cis-regulatory elements changes dramatically at cell-state transitions. Intriguingly, Six1 pre-occupies enhancers of cell-type-specific regulators and effectors before their expression. We demonstrate in-vivo cell-type-specific activity of Six1-bound novel enhancers of Pbx1, Fgf8, Dusp6, Vangl2, the hair-cell master regulator Atoh1 and a cascade of Atoh1's downstream factors, including Pou4f3 and Gfi1. A subset of Six1-bound sites carry consensus-sequences for its downstream factors, including Atoh1, Gfi1, Pou4f3, Gata3 and Pbx1, all of which physically interact with Six1. Motif analysis identifies RFX/X-box as one of the most significantly enriched motifs in Six1-bound sites, and we demonstrate that Six1-RFX proteins cooperatively regulate gene expression through binding to SIX:RFX-motifs. Six1 targets a wide range of hair-bundle regulators and late Six1 deletion disrupts hair-bundle polarity. This study provides a mechanistic understanding of how Six1 cooperates with distinct cofactors in feedforward loops to control lineage-specific gene expression programs during progressive differentiation of the auditory sensory epithelium.","journal":"Nucleic Acids Research","year":2020,"id":62037,"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":53,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.959,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":328290,"name":"Ting Zhang","orcid":"0000-0001-9231-1604","position":1,"is_corresponding":false},{"id":328291,"name":"Aarthi Ramakrishnan","orcid":"0000-0002-6329-6502","position":2,"is_corresponding":false},{"id":328292,"name":"Bernd Fritzsch","orcid":"0000-0002-4882-8398","position":3,"is_corresponding":false},{"id":328293,"name":"Jin Xu","orcid":"0000-0002-6287-5633","position":4,"is_corresponding":false},{"id":330086,"name":"Elaine Y.M. Wong","orcid":null,"position":5,"is_corresponding":false},{"id":328294,"name":"Yong‐Hwee Eddie Loh","orcid":"0000-0002-6185-9279","position":6,"is_corresponding":false},{"id":328295,"name":"Jianqiang Ding","orcid":"0000-0003-1964-1513","position":7,"is_corresponding":false},{"id":328296,"name":"Li Shen","orcid":"0000-0002-5190-2851","position":8,"is_corresponding":false},{"id":328297,"name":"Pin‐Xian Xu","orcid":"0000-0002-8957-6780","position":9,"is_corresponding":false},{"id":328289,"name":"Jun Li","orcid":"0000-0002-1746-6793","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-18T21:10:11.612909Z","pmid":"31956913","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":[]}