{"doi":"10.1161/circulationaha.125.073833","title":"TBX5 and CHD4 Coordinately Activate Atrial Cardiomyocyte Genes to Maintain Cardiac Rhythm Homeostasis","abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:</jats:title>\n                    <jats:p>Atrial fibrillation, the most common sustained arrhythmia, affects 59 million individuals worldwide. The transcription factor TBX5 (T-box 5) is essential for normal atrial rhythm. Its inactivation causes loss of atrial cardiomyocyte (aCM) enhancer accessibility, looping, transcriptional identity, and spontaneous atrial fibrillation. TBX5 interacts with CHD4 (chromodomain helicase DNA-binding protein 4), a chromatin remodeling ATPase canonically associated with the NuRD (nucleosome remodeling and deacetylase) repressor complex.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:</jats:title>\n                    <jats:p>We investigated mechanisms by which TBX5 regulates chromatin organization by studying mice with aCM-selective inactivation of TBX5 or CHD4. We integrated multiple genomics approaches including concurrent single-nucleus transcriptome and open chromatin profiling and genome-wide TBX5 and CHD4 chromatin occupancy assays.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:</jats:title>\n                    <jats:p>\n                      We found that TBX5 recruits CHD4 to 33 170 genomic regions (TBX5-enhanced CHD4 sites). In addition to the canonical repressive activity of CHD4, we uncovered a CHD4 activator function predominantly at sites to which it was recruited by TBX5. TBX5-enhanced CHD4 recruitment increased local chromatin accessibility and promoted the expression of aCM identity genes. This mechanism of CHD4 recruitment by TBX5 was crucial for sinus rhythm; mice with CHD4 inactivation in aCMs had increased atrial fibrillation vulnerability. Assaying TBX5 binding in\n                      <jats:italic toggle=\"yes\">Chd4</jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">AKO</jats:italic>\n                      </jats:sup>\n                      atria demonstrated that CHD4 also promotes TBX5 binding at &gt;10 000 genomic loci, including 3051 TBX5-enhanced CHD4 sites. Consistent with its requirement to maintain normal atrial rhythm, CHD4 was implicated in the regulation of 42 genes linked to atrial fibrillation in humans. Nine had the hallmarks of TBX5-dependent, CHD4-mediated transcriptional activation.\n                    </jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:</jats:title>\n                    <jats:p>Our findings reveal that normal atrial rhythm requires CHD4, which activates and represses atrial genes in a context-dependent manner to maintain aCM gene expression, aCM identity, and atrial rhythm homeostasis.</jats:p>\n                  </jats:sec>","journal":"Circulation","year":2025,"id":602191,"datarank":0.3453877639491069,"base_score":2.302585092994046,"endowment":2.302585092994046,"self_citation_contribution":0.3453877639491069,"citation_network_contribution":0.0,"self_endowment_contribution":0.3453877639491069,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"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":1491315,"name":"Wei Shi","orcid":"0009-0001-2085-0323","position":1,"is_corresponding":false},{"id":353107,"name":"Yan Y. Sweat","orcid":"0000-0002-9903-8054","position":2,"is_corresponding":false},{"id":642886,"name":"Jie Li","orcid":"0000-0002-5271-8263","position":3,"is_corresponding":false},{"id":1544343,"name":"Jiajin Li","orcid":null,"position":4,"is_corresponding":false},{"id":1544344,"name":"Erin M. Keating","orcid":null,"position":5,"is_corresponding":false},{"id":1544345,"name":"Anna Ponek","orcid":"0009-0008-5366-881X","position":6,"is_corresponding":false},{"id":506683,"name":"Qing Ma","orcid":"0000-0002-5625-1330","position":7,"is_corresponding":false},{"id":1544346,"name":"Chaehyoung Park","orcid":null,"position":8,"is_corresponding":false},{"id":662133,"name":"Michael A. Trembley","orcid":"0000-0001-6675-9325","position":9,"is_corresponding":false},{"id":506681,"name":"Yi Wang","orcid":"0000-0002-0291-5314","position":10,"is_corresponding":false},{"id":487189,"name":"Cuilan Hou","orcid":"0000-0003-3972-1625","position":11,"is_corresponding":false},{"id":337473,"name":"Vassilios J. Bezzerides","orcid":"0000-0003-0825-6580","position":12,"is_corresponding":false},{"id":275054,"name":"Frank L. Conlon","orcid":"0000-0002-5027-0397","position":13,"is_corresponding":false},{"id":264279,"name":"William T. Pu","orcid":"0000-0002-4551-8079","position":14,"is_corresponding":false},{"id":353108,"name":"Mason Sweat","orcid":"0000-0002-5400-1266","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"TBX5 and CHD4 Coordinately Activate Atrial Cardiomyocyte Genes to Maintain Cardiac Rhythm Homeostasis","abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:</jats:title>\n                    <jats:p>Atrial fibrillation, the most common sustained arrhythmia, affects 59 million individuals worldwide. The transcription factor TBX5 (T-box 5) is essential for normal atrial rhythm. Its inactivation causes loss of atrial cardiomyocyte (aCM) enhancer accessibility, looping, transcriptional identity, and spontaneous atrial fibrillation. TBX5 interacts with CHD4 (chromodomain helicase DNA-binding protein 4), a chromatin remodeling ATPase canonically associated with the NuRD (nucleosome remodeling and deacetylase) repressor complex.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:</jats:title>\n                    <jats:p>We investigated mechanisms by which TBX5 regulates chromatin organization by studying mice with aCM-selective inactivation of TBX5 or CHD4. We integrated multiple genomics approaches including concurrent single-nucleus transcriptome and open chromatin profiling and genome-wide TBX5 and CHD4 chromatin occupancy assays.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:</jats:title>\n                    <jats:p>\n                      We found that TBX5 recruits CHD4 to 33 170 genomic regions (TBX5-enhanced CHD4 sites). In addition to the canonical repressive activity of CHD4, we uncovered a CHD4 activator function predominantly at sites to which it was recruited by TBX5. TBX5-enhanced CHD4 recruitment increased local chromatin accessibility and promoted the expression of aCM identity genes. This mechanism of CHD4 recruitment by TBX5 was crucial for sinus rhythm; mice with CHD4 inactivation in aCMs had increased atrial fibrillation vulnerability. Assaying TBX5 binding in\n                      <jats:italic toggle=\"yes\">Chd4</jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">AKO</jats:italic>\n                      </jats:sup>\n                      atria demonstrated that CHD4 also promotes TBX5 binding at &gt;10 000 genomic loci, including 3051 TBX5-enhanced CHD4 sites. Consistent with its requirement to maintain normal atrial rhythm, CHD4 was implicated in the regulation of 42 genes linked to atrial fibrillation in humans. Nine had the hallmarks of TBX5-dependent, CHD4-mediated transcriptional activation.\n                    </jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:</jats:title>\n                    <jats:p>Our findings reveal that normal atrial rhythm requires CHD4, which activates and represses atrial genes in a context-dependent manner to maintain aCM gene expression, aCM identity, and atrial rhythm homeostasis.</jats:p>\n                  </jats:sec>","is_dataset_classified":null,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40799140","pmcid":"PMC12479101","openalex_id":"https://openalex.org/W4413112089","authors":[],"funders":[{"funder_name":"NIGMS NIH HHS","grant_id":"P20 GM152326","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"K99 HL173573","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL156503","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R00 HL173573","title":null}],"total_grants":4,"fwci":2.9035,"citation_percentile":0.91428453,"influential_citations":0,"citation_trend":[{"year":2026,"count":7}],"oa_status":"green","license":null,"oa_locations":[{"url":"https://cdr.lib.unc.edu/downloads/73666m913","host_type":"repository"},{"url":"https://cdr.lib.unc.edu/downloads/73666m913","host_type":"repository"},{"url":"https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.125.073833","host_type":"publisher"},{"url":"https://doi.org/10.17615/2kfd-p725","host_type":"repository"},{"url":"https://doi.org/10.1161/circulationaha.125.073833","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40799140","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12479101","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12479101/","host_type":"repository"}],"fields_of_study":["Congenital heart defects research","Genomics and Chromatin Dynamics","Cardiac electrophysiology and arrhythmias"],"mesh_terms":["Animals","Atrial Fibrillation","Heart Atria","Heart Rate","Homeostasis","Humans","T-Box Domain Proteins","Myocytes, Cardiac","Mice","Mi-2 Nucleosome Remodeling and Deacetylase Complex"],"keywords":["Medicine","Homeostasis","Gene","Rhythm","Cell biology","Internal medicine","Cardiology","Genetics","Biology","Transcription factors","Atrial fibrillation","Arrhythmias, Cardiac"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"geo"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-29T18:36:41.806275Z","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":[]}