{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T11:14:06Z","timestamp":1789557246967,"version":"build-2803163510"},"reference-count":54,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","license":[{"start":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T00:00:00Z","timestamp":1684800000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2023,5,23]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Pulmonary arterial hypertension (PAH) is a rare disease characterized by remodeling of the pulmonary arteries, increased vascular resistance, and right-sided heart failure. Genome-wide association studies of idiopathic\/heritable PAH established novel genetic risk variants, including conserved enhancers upstream of transcription factor (TF)\n              <jats:italic>SOX17<\/jats:italic>\n              containing 2 independent signals. SOX17 is an important TF in embryonic development and in the homeostasis of pulmonary artery endothelial cells (hPAEC) in the adult. Rare pathogenic mutations in\n              <jats:italic>SOX17<\/jats:italic>\n              cause heritable PAH. We hypothesized that PAH risk alleles in an enhancer region impair TF-binding upstream of\n              <jats:italic>SOX17<\/jats:italic>\n              , which in turn reduces\n              <jats:italic>SOX17<\/jats:italic>\n              expression and contributes to disturbed endothelial cell function and PAH development.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              CRISPR manipulation and siRNA were used to modulate\n              <jats:italic>SOX17<\/jats:italic>\n              expression. Electromobility shift assays were used to confirm in silico\n              <jats:italic>\u2013<\/jats:italic>\n              predicted TF differential binding to the\n              <jats:italic>SOX17<\/jats:italic>\n              variants. Functional assays in hPAECs were used to establish the biological consequences of\n              <jats:italic>SOX17<\/jats:italic>\n              loss. In silico analysis with the connectivity map was used to predict compounds that rescue disturbed\n              <jats:italic>SOX17<\/jats:italic>\n              signaling. Mice with deletion of the\n              <jats:italic>SOX17<\/jats:italic>\n              -signal 1 enhancer region (\n              <jats:italic>SOX17<\/jats:italic>\n              -4593\/enhKO) were phenotyped in response to chronic hypoxia and SU5416\/hypoxia.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              CRISPR inhibition of\n              <jats:italic>SOX17<\/jats:italic>\n              -signal 2 and deletion of\n              <jats:italic>SOX17<\/jats:italic>\n              -signal 1 specifically decreased\n              <jats:italic>SOX17<\/jats:italic>\n              expression. Electromobility shift assays demonstrated differential binding of hPAEC nuclear proteins to the risk and nonrisk alleles from both\n              <jats:italic>SOX17<\/jats:italic>\n              signals. Candidate TFs HOXA5 and ROR-\u03b1 were identified through in silico analysis and antibody electromobility shift assays. Analysis of the hPAEC transcriptomes revealed alteration of PAH-relevant pathways on\n              <jats:italic>SOX17<\/jats:italic>\n              silencing, including extracellular matrix regulation.\n              <jats:italic>SOX17<\/jats:italic>\n              silencing in hPAECs resulted in increased apoptosis, proliferation, and disturbance of barrier function. With the use of the connectivity map, compounds were identified that reversed the SOX17-dysfunction transcriptomic signatures in hPAECs.\n              <jats:italic>SOX17<\/jats:italic>\n              enhancer knockout in mice reduced lung SOX17 expression, resulting in more severe pulmonary vascular leak and hypoxia or SU5416\/hypoxia-induced pulmonary hypertension.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              Common PAH risk variants upstream of the\n              <jats:italic>SOX17<\/jats:italic>\n              promoter reduce endothelial\n              <jats:italic>SOX17<\/jats:italic>\n              expression, at least in part, through differential binding of HOXA5 and ROR-\u03b1. Reduced SOX17 expression results in disturbed hPAEC function and PAH. Existing drug compounds can reverse the disturbed SOX17 pulmonary endothelial transcriptomic signature.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.122.061940","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T09:08:37Z","timestamp":1681722517000},"page":"1606-1621","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":48,"title":["<i>SOX17<\/i>\n            Enhancer Variants Disrupt Transcription Factor Binding And Enhancer Inactivity Drives Pulmonary Hypertension"],"prefix":"10.1161","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0743-9070","authenticated-orcid":true,"given":"Rachel","family":"Walters","sequence":"first","affiliation":[{"name":"National Heart and Lung Institute, Hammersmith Hospital, Imperial College, London, United Kingdom (R.W., E.V., J.A., C.-N.C., Y.W., A.A., O.D., L.Z., F.S., M.R.W., L.Z., C.J.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Vasilaki","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Hammersmith Hospital, Imperial College, London, United Kingdom (R.W., E.V., J.A., C.-N.C., Y.W., A.A., O.D., L.Z., F.S., M.R.W., L.Z., C.J.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6211-1791","authenticated-orcid":true,"given":"Jurjan","family":"Aman","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Hammersmith Hospital, Imperial College, London, United Kingdom (R.W., E.V., J.A., C.-N.C., Y.W., A.A., O.D., L.Z., F.S., M.R.W., L.Z., C.J.R.)."},{"name":"Department of Pulmonary Medicine, Amsterdam University Medical Center, The Netherlands (J.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Nien","family":"Chen","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Hammersmith Hospital, Imperial College, London, United Kingdom (R.W., E.V., J.A., C.-N.C., Y.W., A.A., O.D., L.Z., F.S., M.R.W., L.Z., C.J.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukyee","family":"Wu","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Hammersmith Hospital, Imperial College, London, United Kingdom (R.W., E.V., J.A., C.-N.C., Y.W., A.A., O.D., L.Z., F.S., M.R.W., L.Z., C.J.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2266-6722","authenticated-orcid":true,"given":"Olin D.","family":"Liang","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine (O.D.L.), Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Ashek","sequence":"additional","affiliation":[{"name":"National Heart and Lung 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Digestion &amp; Reproduction, Hammersmith Hospital, Imperial College, London, United Kingdom (I.C., J.F.)."},{"name":"Computational Biology and Health Genomics Programme, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Spain (J.F.)."},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Diabetes y Enfermedades Metab\u00f3licas Asociadas, Barcelona, Spain (J.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5700-9792","authenticated-orcid":true,"given":"Nicholas W.","family":"Morrell","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, United Kingdom (N.W.M.)."},{"name":"NIHR BioResource for Translational Research, University of Cambridge, United Kingdom (N.W.M.)."},{"name":"On Behalf of the British Heart Foundation\/Medical Research Council UK PAH Cohort Consortium (N.W.M., M.R.W., 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