{"doi":"10.1101/2023.10.22.563497","title":"Master transcription factor binding sites constitute the core of early replication control elements","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>Eukaryotic genomes replicate in a defined temporal order called the replication timing (RT) program. RT is developmentally regulated with potential to drive cell fate transitions, but mechanisms controlling RT remain elusive. We previously identified “Early Replication Control Elements” (ERCEs) necessary for early RT, domain-wide transcription, 3D chromatin architecture and compartmentalization in mouse embryonic stem cells (mESCs) but, deletions identifying ERCEs were large and encompassed many putative regulatory elements. Here, we show that ERCEs are compound elements whose RT activity can largely be accounted for by multiple sites of diverse master transcription factor binding (subERCEs), distinguished from other such sites by their long-range interactions. While deletion of subERCEs had large effects on both transcription and RT, deleting transcription start sites eliminated nearly all transcription with moderate effects on RT. Our results suggest a model in which subERCEs respond to diverse master transcription factors by functioning both as transcription enhancers and as elements that organize chromatin domains structurally and support early RT, potentially providing a feed-forward loop to drive robust epigenomic change during cell fate transitions.</jats:p>","journal":null,"year":null,"id":680166,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"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":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1109870,"name":"Laura Hinojosa-Gonzalez","orcid":"0009-0006-3812-887X","position":1,"is_corresponding":false},{"id":43147,"name":"Takayo Sasaki","orcid":"0000-0001-7609-9316","position":2,"is_corresponding":false},{"id":1392001,"name":"Satoshi Uchino","orcid":"0000-0003-1444-0130","position":3,"is_corresponding":false},{"id":1777104,"name":"Athanasios Vouzas","orcid":null,"position":4,"is_corresponding":false},{"id":1777105,"name":"Mariella S. Soto","orcid":null,"position":5,"is_corresponding":false},{"id":411362,"name":"Abhijit Chakraborty","orcid":"0000-0002-3822-5657","position":6,"is_corresponding":false},{"id":542940,"name":"Karen E. Alexander","orcid":"0000-0003-1015-3361","position":7,"is_corresponding":false},{"id":1392537,"name":"Cheryl A. Fitch","orcid":null,"position":8,"is_corresponding":false},{"id":278542,"name":"Amber N. Brown","orcid":"0000-0003-1171-5346","position":9,"is_corresponding":false},{"id":45041,"name":"Ferhat Ay","orcid":"0000-0002-0708-6914","position":10,"is_corresponding":false},{"id":42992,"name":"David M. Gilbert","orcid":"0000-0001-8087-9737","position":11,"is_corresponding":false},{"id":1173564,"name":"Jesse L. Turner","orcid":"0000-0003-1149-5160","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Master transcription-factor binding sites constitute the core of early replication control elements","abstract":"<jats:title>Abstract</jats:title>                   <jats:p>Eukaryotic genomes replicate in a defined temporal order called the replication timing (RT) program. RT is developmentally regulated with the potential to drive cell fate transitions, but mechanisms controlling RT remain elusive. We previously identified “Early Replication Control Elements” (ERCEs), cis-acting elements necessary for early RT, domain-wide transcription, 3D chromatin architecture and compartmentalization in mouse embryonic stem cells (mESCs), but deletions identifying ERCEs were large and encompassed many putative regulatory elements. Here, we show that ERCEs are compound elements, whose RT activity can largely be accounted for by multiple binding sites for diverse master transcription factors (subERCEs). While deletion of subERCEs had large effects on both transcription and replication timing, deleting transcription start sites eliminated nearly all transcription with only moderate effects on replication timing. Our results suggest a model in which subERCEs are a class of transcriptional enhancers that can also organize chromatin domains structurally to support early replication timing, potentially providing a feed-forward loop to drive robust epigenomic change during cell fate transitions.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39990485","pmcid":null,"openalex_id":null,"authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"5F31AG066481-02","title":"Genetic dissection of cis-acting elements controlling DNA replication timing and genome architecture"},{"funder_name":"National Institutes of Health","grant_id":"2R01GM083337-13","title":"cis-Acting Elements Regulating Developmental Control of Replication Timing"},{"funder_name":"National Institutes of Health","grant_id":"3R35GM128938-07S1","title":"Studying the function of human genetic variation in the light of 3D genome organization"},{"funder_name":"National Institutes of Health","grant_id":"5T32GM139790-05","title":"Graduate Training Program in Bioinformatics"}],"total_grants":4,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"CC BY","oa_locations":[{"url":"https://doi.org/10.1038/s44318-025-00501-5","host_type":""},{"url":"https://doi.org/10.1101/2023.10.22.563497","host_type":""},{"url":"https://dx.doi.org/10.5281/zenodo.15678081","host_type":""},{"url":"https://dx.doi.org/10.5281/zenodo.15678082","host_type":""},{"url":"http://dx.doi.org/10.5281/zenodo.15678082","host_type":""},{"url":"https://zenodo.org/records/15678082","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/40676214","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/39990485","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/40676214/","host_type":""},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12361434/","host_type":""}],"fields_of_study":["0301 basic medicine","03 medical and health sciences"],"mesh_terms":[],"keywords":["DNA Replication","Mice","Binding Sites","Transcription, Genetic","DNA Replication Timing","Animals","Mouse Embryonic Stem Cells","Article","Chromatin","Transcription Factors"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-17T14:33:36.556734Z","pmid":null,"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":[]}