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Here we show that Engrailed 1 (EN1) is reexpressed in multiple fibroblast subpopulations in the skin of SSc patients. We characterize EN1 as a molecular amplifier of TGF\u03b2 signaling in myofibroblast differentiation: TGF\u03b2 induces EN1 expression in a SMAD3-dependent manner, and in turn, EN1 mediates the profibrotic effects of TGF\u03b2. RNA sequencing demonstrates that EN1 induces a profibrotic gene expression profile functionally related to cytoskeleton organization and ROCK activation. EN1 regulates gene expression by modulating the activity of SP1 and other SP transcription factors, as confirmed by ChIP-seq experiments for EN1 and SP1. Functional experiments confirm the coordinating role of EN1 on ROCK activity and the reorganization of cytoskeleton during myofibroblast differentiation, in both standard fibroblast culture systems and in vitro skin models. Consistently, mice with fibroblast-specific knockout of En1 demonstrate impaired fibroblast-to-myofibroblast transition and are partially protected from experimental skin fibrosis.<\/jats:p>","DOI":"10.1084\/jem.20201916","type":"journal-article","created":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T02:21:40Z","timestamp":1621909300000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":51,"title":["Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4960-3369","authenticated-orcid":true,"given":"Andrea-Hermina","family":"Gy\u00f6rfi","sequence":"first","affiliation":[{"name":"Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-N\u00fcrnberg and University Hospital Erlangen, Erlangen, Germany 1"},{"name":"Deutsches Zentrum f\u00fcr Immuntherapie, Friedrich-Alexander-University Erlangen-N\u00fcrnberg and University Hospital Erlangen, Erlangen, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1248-3145","authenticated-orcid":true,"given":"Alexandru-Emil","family":"Matei","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-N\u00fcrnberg and University Hospital Erlangen, Erlangen, Germany 1"},{"name":"Deutsches Zentrum f\u00fcr Immuntherapie, Friedrich-Alexander-University Erlangen-N\u00fcrnberg and University Hospital Erlangen, Erlangen, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8099-9541","authenticated-orcid":true,"given":"Maximilian","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Medical Informatics, Friedrich-Alexander University of Erlangen-N\u00fcrnberg, Erlangen, Germany 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0305-2522","authenticated-orcid":true,"given":"Chunguang","family":"Liang","sequence":"additional","affiliation":[{"name":"Medical Informatics, Friedrich-Alexander University of Erlangen-N\u00fcrnberg, Erlangen, Germany 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0871-306X","authenticated-orcid":true,"given":"Aleix Rius","family":"Rigau","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-N\u00fcrnberg and University Hospital Erlangen, Erlangen, Germany 1"},{"name":"Deutsches Zentrum f\u00fcr Immuntherapie, Friedrich-Alexander-University Erlangen-N\u00fcrnberg and University Hospital Erlangen, Erlangen, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3268-7404","authenticated-orcid":true,"given":"Xuezhi","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-N\u00fcrnberg and University Hospital Erlangen, Erlangen, Germany 1"},{"name":"Deutsches Zentrum f\u00fcr Immuntherapie, Friedrich-Alexander-University Erlangen-N\u00fcrnberg and University Hospital Erlangen, Erlangen, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9322-5684","authenticated-orcid":true,"given":"Honglin","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-N\u00fcrnberg and University Hospital Erlangen, Erlangen, Germany 1"},{"name":"Deutsches Zentrum f\u00fcr Immuntherapie, Friedrich-Alexander-University Erlangen-N\u00fcrnberg and University Hospital Erlangen, Erlangen, Germany 2"},{"name":"Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. 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