{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T17:15:13Z","timestamp":1774631713948,"version":"3.50.1"},"posted":{"date-parts":[[2023,1,7]]},"group-title":"Molecular Biology","reference-count":50,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,1,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Chronic inflammation and tissue fibrosis are common stress responses that worsen organ function, yet the molecular mechanisms governing their crosstalk are poorly understood. In diseased organs, stress-induced changes in gene expression fuel maladaptive cell state transitions and pathological interaction between diverse cellular compartments. Although chronic fibroblast activation worsens dysfunction of lung, liver, kidney, and heart, and exacerbates many cancers, the stress-sensing mechanisms initiating the transcriptional activation of fibroblasts are not well understood. Here, we show that conditional deletion of the transcription co-activator\n                  <jats:italic>Brd4<\/jats:italic>\n                  in\n                  <jats:italic>Cx3cr1<\/jats:italic>\n                  -positive myeloid cells ameliorates heart failure and is associated with a dramatic reduction in fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy\n                  <jats:italic>in vivo<\/jats:italic>\n                  in\n                  <jats:italic>Cx3cr1<\/jats:italic>\n                  -positive cells identified a large enhancer proximal to\n                  <jats:italic>Interleukin-1 beta (Il1b)<\/jats:italic>\n                  , and a series of CRISPR deletions revealed the precise stress-dependent regulatory element that controlled expression of\n                  <jats:italic>Il1b<\/jats:italic>\n                  in disease. Secreted IL1B functioned non-cell autonomously to activate a p65\/RELA-dependent enhancer near the transcription factor\n                  <jats:italic>MEOX1<\/jats:italic>\n                  , resulting in a profibrotic response in human cardiac fibroblasts.\n                  <jats:italic>In vivo<\/jats:italic>\n                  , antibody-mediated IL1B neutralization prevented stress-induced expression of\n                  <jats:italic>MEOX1<\/jats:italic>\n                  , inhibited fibroblast activation, and improved cardiac function in heart failure. The elucidation of BRD4-dependent crosstalk between a specific immune cell subset and fibroblasts through IL1B provides new therapeutic strategies for heart disease and other disorders of chronic inflammation and maladaptive tissue remodeling.\n                <\/jats:p>","DOI":"10.1101\/2023.01.06.522937","type":"posted-content","created":{"date-parts":[[2023,1,7]],"date-time":"2023-01-07T22:25:12Z","timestamp":1673130312000},"source":"Crossref","is-referenced-by-count":12,"title":["Chromatin Remodeling Drives Immune-Fibroblast Crosstalk in Heart Failure Pathogenesis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6224-6354","authenticated-orcid":false,"given":"Michael","family":"Alexanian","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arun","family":"Padmanabhan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomohiro","family":"Nishino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua G.","family":"Travers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Ye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara Youngna","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nandhini","family":"Sadagopan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelo","family":"Pelonero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirsten","family":"Auclair","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ada","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Gonzalez Teran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Will","family":"Flanigan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charis Kee-Seon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koya","family":"Lumbao-Conradson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mauro","family":"Costa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajan","family":"Jain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Israel","family":"Charo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saptarsi M.","family":"Haldar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine S.","family":"Pollard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald J.","family":"Vagnozzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy A.","family":"McKinsey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pawel F.","family":"Przytycki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepak","family":"Srivastava","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023010905350678000_2023.01.06.522937v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3545"},{"key":"2023010905350678000_2023.01.06.522937v1.2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41392-020-00384-4","article-title":"The BET family in immunity and disease","volume":"6","year":"2021","journal-title":"Signal Transduct Target Ther"},{"key":"2023010905350678000_2023.01.06.522937v1.3","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/s41586-021-03674-1","article-title":"A transcriptional switch governs fibroblast activation in heart disease","volume":"595","year":"2021","journal-title":"Nature"},{"key":"2023010905350678000_2023.01.06.522937v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nature09504"},{"key":"2023010905350678000_2023.01.06.522937v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.07.013"},{"key":"2023010905350678000_2023.01.06.522937v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2013.07.017"},{"key":"2023010905350678000_2023.01.06.522937v1.7","doi-asserted-by":"crossref","unstructured":"Duan, Q. et al. 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