{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T23:05:31Z","timestamp":1792710331909,"version":"4.5.0"},"reference-count":49,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T00:00:00Z","timestamp":1625616000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["K24AR063120"],"award-info":[{"award-number":["K24AR063120"]}],"id":[{"id":"10.13039\/100000069","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":["R01AR070148"],"award-info":[{"award-number":["R01AR070148"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI097134"],"award-info":[{"award-number":["R01AI097134"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Systemic sclerosis (SSc) is characterized by widespread fibrosis and vascular complications. This study was undertaken to examine the chromatin landscape and transcription factor footprints in SSc, using an assay for genome\u2010wide chromatin accessibility.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Dermal endothelial cells (ECs) and fibroblasts were isolated from healthy controls and patients with diffuse cutaneous SSc (dcSSc). Assay for transposase\u2010accessible chromatin with sequencing (ATAC\u2010seq) was performed to assess genome\u2010wide chromatin accessibility at a read depth of ~150 million reads per sample. Transcription factor footprinting and motif binding analysis were performed, followed by functional experiments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Chromatin accessibility was significantly reduced in dcSSc patients compared to healthy controls. Differentially accessible chromatin loci were enriched in pathways and gene ontologies involved in the nervous system, cell membrane projections and cilia motility, nuclear and steroid receptors, and nitric oxide. In addition, chromatin binding of transcription factors SNAI2, ETV2, and ELF1 was significantly increased in dcSSc ECs, while recruitment of RUNX1 and RUNX2 was enriched in dcSSc fibroblasts. We found significant down\u2010regulation of the neuronal gene\n                      <jats:italic>NRXN1<\/jats:italic>\n                      and up\u2010regulation of\n                      <jats:italic>SNAI2<\/jats:italic>\n                      and\n                      <jats:italic>ETV2<\/jats:italic>\n                      in dcSSc ECs. In dcSSc fibroblasts, down\u2010regulation of the neuronal gene\n                      <jats:italic>ENTPD1<\/jats:italic>\n                      and up\u2010regulation of\n                      <jats:italic>RUNX2<\/jats:italic>\n                      were confirmed. Further functional analysis revealed that ETV2 and NRXN1 dysregulation affected angiogenesis in ECs, while ENTPD1 enhanced profibrotic properties in dcSSc fibroblasts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our data identify the chromatin blueprint of dcSSc, and suggest that neuronal\u2010related characteristics of SSc ECs and fibroblasts could be a culprit for dysregulated angiogenesis and enhanced fibrosis. Targeting the key pathways and transcription factors identified might present novel therapeutic approaches in SSc.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.41694","type":"journal-article","created":{"date-parts":[[2021,2,15]],"date-time":"2021-02-15T02:29:13Z","timestamp":1613356153000},"page":"1501-1513","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Genome\u2010Wide Reduction in Chromatin Accessibility and Unique Transcription Factor Footprints in Endothelial Cells and Fibroblasts in Scleroderma Skin"],"prefix":"10.1002","volume":"73","author":[{"given":"Pei\u2010Suen","family":"Tsou","sequence":"first","affiliation":[{"name":"University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela J.","family":"Palisoc","sequence":"additional","affiliation":[{"name":"University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Ali","sequence":"additional","affiliation":[{"name":"University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1412-4453","authenticated-orcid":false,"given":"Dinesh","family":"Khanna","sequence":"additional","affiliation":[{"name":"University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3884-962X","authenticated-orcid":false,"given":"Amr H.","family":"Sawalha","sequence":"additional","affiliation":[{"name":"University of Pittsburgh  Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,7,7]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2017.05.004"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.11173"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2014-205303"},{"key":"e_1_2_6_5_1","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1136\/annrheumdis-2018-213022","article-title":"Methyl\u2010CpG\u2010binding protein 2 mediates antifibrotic effects in scleroderma fibroblasts","volume":"77","author":"He Y","year":"2018","journal-title":"Ann Rheum Dis"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1813006116"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39828"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq466"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkj143"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201439939"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.05.052"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03856-y"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20170416"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-214499"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.21948"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1177\/1358836X0000500304"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-210229"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41536"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11926-019-0822-0"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00626"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diff.2011.11.007"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780380102"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0889-857X(05)70306-9"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-060909-152829"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-213239"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-015-0749-4"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.146.1.233"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-0987-1"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0809510106"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00260.2017"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00206.2017"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1084"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11302-019-09664-3"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e08-05-0506"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3006927"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.143420"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1413234112"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-07559-0"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/oncsis.2016.17"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.080382"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.01.035"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2013.06.016"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210959"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm905"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2009-0379"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M500608200"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.04.021"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.306341"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201700482R"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-214991"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.41694","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/art.41694","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.41694","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T20:02:54Z","timestamp":1759953774000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.41694"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,7]]},"references-count":49,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2021,8]]}},"alternative-id":["10.1002\/art.41694"],"URL":"https:\/\/doi.org\/10.1002\/art.41694","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.06.24.20138040","asserted-by":"object"}]},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,7]]},"assertion":[{"value":"2020-07-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-02-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-07-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}