{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T14:56:19Z","timestamp":1792508179724,"version":"4.5.0"},"reference-count":44,"publisher":"European Respiratory Society (ERS)","issue":"1","license":[{"start":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T00:00:00Z","timestamp":1683158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.ersjournals.com\/user-licence"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01 HL 126990"],"award-info":[{"award-number":["R01 HL 126990"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["P50 AR 060780-06A1"],"award-info":[{"award-number":["P50 AR 060780-06A1"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100003284","name":"Pulmonary Fibrosis Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003284","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019921","name":"National Scleroderma Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100019921","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["Eur Respir J"],"accepted":{"date-parts":[[2023,4,20]]},"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>In idiopathic pulmonary fibrosis (IPF), myofibroblasts are key effectors of fibrosis and architectural distortion by excessive deposition of extracellular matrix and their acquired contractile capacity. Single-cell RNA-sequencing (scRNA-seq) has precisely defined the IPF myofibroblast transcriptome, but identifying critical transcription factor activity by this approach is imprecise.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed single-nucleus assay for transposase-accessible chromatin sequencing on explanted lungs from patients with IPF (n=3) and donor controls (n=2) and integrated this with a larger scRNA-seq dataset (10 IPF, eight controls) to identify differentially accessible chromatin regions and enriched transcription factor motifs within lung cell populations. We performed RNA-sequencing on pulmonary fibroblasts of bleomycin-injured\n                      <jats:italic>Twist1-<\/jats:italic>\n                      overexpressing COL1A2 Cre-ER mice to examine alterations in fibrosis-relevant pathways following\n                      <jats:italic>Twist1<\/jats:italic>\n                      overexpression in collagen-producing cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TWIST1, and other E-box transcription factor motifs, were significantly enriched in open chromatin of IPF myofibroblasts compared to both IPF nonmyogenic (log\n                      <jats:sub>2<\/jats:sub>\n                      fold change (FC) 8.909, adjusted p-value 1.82\u00d710\n                      <jats:sup>\u221235<\/jats:sup>\n                      ) and control fibroblasts (log\n                      <jats:sub>2<\/jats:sub>\n                      FC 8.975, adjusted p-value 3.72\u00d710\n                      <jats:sup>\u221228<\/jats:sup>\n                      ).\n                      <jats:italic>TWIST1<\/jats:italic>\n                      expression was selectively upregulated in IPF myofibroblasts (log\n                      <jats:sub>2<\/jats:sub>\n                      FC 3.136, adjusted p-value 1.41\u00d710\n                      <jats:sup>\u2212<\/jats:sup>\n                      <jats:sup>24<\/jats:sup>\n                      ), with two regions of\n                      <jats:italic>TWIST1<\/jats:italic>\n                      having significantly increased accessibility in IPF myofibroblasts. Overexpression of Twist1 in COL1A2-expressing fibroblasts of bleomycin-injured mice resulted in increased collagen synthesis and upregulation of genes with enriched chromatin accessibility in IPF myofibroblasts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our studies utilising human multiomic single-cell analyses combined with\n                      <jats:italic>in vivo<\/jats:italic>\n                      murine disease models confirm a critical regulatory function for TWIST1 in IPF myofibroblast activity in the fibrotic lung. Understanding the global process of opening TWIST1 and other E-box transcription factor motifs that govern myofibroblast differentiation may identify new therapeutic interventions for fibrotic pulmonary diseases.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1183\/13993003.00474-2022","type":"journal-article","created":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T13:15:23Z","timestamp":1683206123000},"page":"2200474","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":35,"title":["Single-nucleus chromatin accessibility identifies a critical role for TWIST1 in idiopathic pulmonary fibrosis myofibroblast 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