{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T13:30:24Z","timestamp":1792762224232,"version":"4.5.0"},"reference-count":58,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"729","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2024,1,10]]},"abstract":"<jats:p>\n            Hypoxic reprogramming of vasculature relies on genetic, epigenetic, and metabolic circuitry, but the control points are unknown. In pulmonary arterial hypertension (PAH), a disease driven by hypoxia inducible factor (HIF)\u2013dependent vascular dysfunction, HIF-2\u03b1 promoted expression of neighboring genes, long noncoding RNA (lncRNA) histone lysine\n            <jats:italic>N<\/jats:italic>\n            -methyltransferase 2E-antisense 1 (\n            <jats:italic>KMT2E-AS1<\/jats:italic>\n            ) and histone lysine N-methyltransferase 2E (\n            <jats:italic>KMT2E<\/jats:italic>\n            ).\n            <jats:italic>KMT2E-AS1<\/jats:italic>\n            stabilized KMT2E protein to increase epigenetic histone 3 lysine 4 trimethylation (H3K4me3), driving HIF-2\u03b1\u2013dependent metabolic and pathogenic endothelial activity. This lncRNA axis also increased HIF-2\u03b1 expression across epigenetic, transcriptional, and posttranscriptional contexts, thus promoting a positive feedback loop to further augment HIF-2\u03b1 activity. We identified a genetic association between rs73184087, a single-nucleotide variant (SNV) within a\n            <jats:italic>KMT2E<\/jats:italic>\n            intron, and disease risk in PAH discovery and replication patient cohorts and in a global meta-analysis. This SNV displayed allele (G)\u2013specific association with HIF-2\u03b1, engaged in long-range chromatin interactions, and induced the lncRNA-KMT2E tandem in hypoxic (G\/G) cells. In vivo,\n            <jats:italic>KMT2E-AS1<\/jats:italic>\n            deficiency protected against PAH in mice, as did pharmacologic inhibition of histone methylation in rats. Conversely, forced lncRNA expression promoted more severe PH. Thus, the\n            <jats:italic>KMT2E-AS1<\/jats:italic>\n            \/KMT2E pair orchestrates across convergent multi-ome landscapes to mediate HIF-2\u03b1 pathobiology and represents a key clinical target in pulmonary hypertension.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.add2029","type":"journal-article","created":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T18:58:47Z","timestamp":1704913127000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":28,"title":["Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3674-0783","authenticated-orcid":true,"given":"Yi-Yin","family":"Tai","sequence":"first","affiliation":[{"name":"Center for Pulmonary Vascular Biology and Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Division of Cardiology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0690-138X","authenticated-orcid":true,"given":"Qiujun","family":"Yu","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Tang","sequence":"additional","affiliation":[{"name":"Center for Pulmonary Vascular Biology and Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Division of Cardiology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5255-1213","authenticated-orcid":true,"given":"Wei","family":"Sun","sequence":"additional","affiliation":[{"name":"Center for Pulmonary Vascular Biology and Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Division of Cardiology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0455-5348","authenticated-orcid":true,"given":"Neil J.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Center for Pulmonary Vascular Biology and Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Division of Cardiology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Pittsburgh VA Medical Center, Pittsburgh, PA 15240, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Okawa","sequence":"additional","affiliation":[{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Division of Cardiology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Department of Computational and Systems Biology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15219, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingsi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Center for Pulmonary Vascular Biology and Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Division of Cardiology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA."},{"name":"Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, 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