{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T04:31:59Z","timestamp":1792729919773,"version":"4.5.0"},"reference-count":77,"publisher":"National Academy of Sciences","issue":"19","license":[{"start":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T00:00:00Z","timestamp":1682899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["185655"],"award-info":[{"award-number":["185655"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,5,9]]},"abstract":"<jats:p>\n                    Narcolepsy with cataplexy is\u00a0a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin\/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to\u00a0\n                    <jats:italic>Hcrt,<\/jats:italic>\n                    <jats:italic>Qrfp<\/jats:italic>\n                    transcript is also lost in the lateral hypothalamus, while in mice where only the\u00a0\n                    <jats:italic>Hcrt<\/jats:italic>\n                    \u00a0gene is inactivated\n                    <jats:italic>Qrfp<\/jats:italic>\n                    is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved\u00a0\n                    <jats:italic>QRFP<\/jats:italic>\n                    \u00a0expression, suggesting the neurons are present but fail to actively produce HCRT. We show that the promoter of the\u00a0\n                    <jats:italic>HCRT<\/jats:italic>\n                    \u00a0gene of patients exhibits hypermethylation at a methylation-sensitive and evolutionary-conserved PAX5:ETS1 transcription factor-binding site, suggesting the gene is\u00a0subject to transcriptional silencing. We show also that in addition to HCRT,\u00a0\n                    <jats:italic>CRH<\/jats:italic>\n                    \u00a0and Dynorphin (\n                    <jats:italic>PDYN<\/jats:italic>\n                    ) gene promoters, exhibit hypermethylation in the hypothalamus of patients. Altogether, we propose that\n                    <jats:italic>HCRT<\/jats:italic>\n                    ,\u00a0\n                    <jats:italic>PDYN<\/jats:italic>\n                    , and\u00a0\n                    <jats:italic>CRH<\/jats:italic>\n                    are epigenetically silenced by a hypothalamic assault (inflammation) in narcolepsy patients,\u00a0without concurrent cell death. Since methylation is reversible, our findings open the prospect of reversing or curing narcolepsy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2220911120","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T15:11:27Z","timestamp":1682953887000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":65,"title":["Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy"],"prefix":"10.1073","volume":"120","author":[{"given":"Ali","family":"Seifinejad","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2159-6910","authenticated-orcid":false,"given":"Mergim","family":"Ramosaj","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Shan","sequence":"additional","affiliation":[{"name":"Sleep-Wake Centre Stichting Epilepsie Instellingen Nederland, 2103SW Heemstede, The Netherlands"},{"name":"Department of Neurology, Leiden University Medical Center, 2333ZA Leiden, The Netherlands"},{"name":"Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam 1105 BA, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4962-0748","authenticated-orcid":false,"given":"Marie-Laure","family":"Possovre","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4932-1343","authenticated-orcid":false,"given":"Corinne","family":"Pfister","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1935-7603","authenticated-orcid":false,"given":"Rolf","family":"Fronczek","sequence":"additional","affiliation":[{"name":"Sleep-Wake Centre Stichting Epilepsie Instellingen Nederland, 2103SW Heemstede, The Netherlands"},{"name":"Department of Neurology, Leiden University Medical Center, 2333ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7806-4352","authenticated-orcid":false,"given":"Lee\u00a0A.","family":"Garrett-Sinha","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY 14260-1660"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8472-3705","authenticated-orcid":false,"given":"David","family":"Frieser","sequence":"additional","affiliation":[{"name":"Infinity\u2013Institut Toulousain des Maladies Infectieuses et Inflammatoires, Universit\u00e9 de Toulouse, CNRS, INSERM, Universit\u00e9 Paul Sabatier, 31059 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5087-6367","authenticated-orcid":false,"given":"Makoto","family":"Honda","sequence":"additional","affiliation":[{"name":"Sleep Disorders Project, Tokyo Metropolitan Institute of Medical Science, 156-8506 Tokyo, Japan"},{"name":"Institute of Neuropsychiatry, Seiwa Hospital, 162-0851, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoan","family":"Arribat","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3683-4459","authenticated-orcid":false,"given":"Dogan","family":"Grepper","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Amati","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Picot","sequence":"additional","affiliation":[{"name":"Normandie Univ, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1223-5619","authenticated-orcid":false,"given":"Andrea","family":"Agnoletto","sequence":"additional","affiliation":[{"name":"Institut Suisse de Recherche Exp\u00e9rimentale sur le Cancer, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne, 1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2296-2863","authenticated-orcid":false,"given":"Christian","family":"Iseli","sequence":"additional","affiliation":[{"name":"Bioinformatic Competence Center, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne, 1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Chartrel","sequence":"additional","affiliation":[{"name":"Normandie Univ, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5477-5475","authenticated-orcid":false,"given":"Roland","family":"Liblau","sequence":"additional","affiliation":[{"name":"Infinity\u2013Institut Toulousain des Maladies Infectieuses et Inflammatoires, Universit\u00e9 de Toulouse, CNRS, INSERM, Universit\u00e9 Paul Sabatier, 31059 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert\u00a0J.","family":"Lammers","sequence":"additional","affiliation":[{"name":"Sleep-Wake Centre Stichting Epilepsie Instellingen Nederland, 2103SW Heemstede, The Netherlands"},{"name":"Department of Neurology, Leiden University Medical Center, 2333ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5314-5620","authenticated-orcid":false,"given":"Anne","family":"Vassalli","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6997-3914","authenticated-orcid":false,"given":"Mehdi","family":"Tafti","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1005, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,5]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0226-9"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/79690"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)00058-1"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(99)05582-8"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.5665\/sleep.3300"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.372"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/33.11.1428"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0540-1"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13234-x"},{"key":"e_1_3_4_10_2","first-page":"A315","article-title":"Sleepiness due to Wernicke\u2019s encephalopathy with bilateral hypothalamic lesion in a 5-year-old girl","volume":"27","author":"Kashiwagi T. T.","year":"2004","unstructured":"T. T. Kashiwagi , Sleepiness due to Wernicke\u2019s encephalopathy with bilateral hypothalamic lesion in a 5-year-old girl. Sleep 27, A315 (2004).","journal-title":"Sleep"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-004-0442-z"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sleep.2007.11.022"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000276948.46213.64"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awm109"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181bd1344"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.5665\/sleep.5642"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26300"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx093"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.08.007"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsy019"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsz198"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1902148116"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0073-14.2014"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0004254"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep12584"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0164716"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4462"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2011.08.002"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2163-6"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.25.17771"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M107962200"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000175219.01544.c8"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000168173.71940.ab"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aad2353"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501076102"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2642"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.10.17.2198"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-010-0642-1"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.6.1946-1960.2003"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90079-5"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-020-01616-7"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0703806104"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0811126106"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1284-12.2012"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8986.1995.tb02957.x"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4332-06.2006"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI41366"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.207654.112"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aao4953"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2112225119"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00644-X"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/29680"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13104-022-06121-0"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440-1819.2001.00782.x"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-0039.1999.540204.x"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.166.16.1739"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sleep.2013.04.030"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2010.11.003"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2007.06.008"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awu069"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv010"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-016-0254-x"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2014.08.010"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abh3021"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.03.022"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.01.012"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/377635a0"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000168173.71940.ab"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24019"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2010.12.008"},{"key":"e_1_3_4_71_2","first-page":"1305","article-title":"Hypothalamic immunopathology in anti-Ma-associated diencephalitis with narcolepsy-cataplexy","volume":"70","author":"Dauvilliers Y.","year":"2013","unstructured":"Y. Dauvilliers , Hypothalamic immunopathology in anti-Ma-associated diencephalitis with narcolepsy-cataplexy. JAMA Neurol. 70, 1305\u20131310 (2013).","journal-title":"JAMA Neurol."},{"key":"e_1_3_4_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibtech.2018.12.002"},{"key":"e_1_3_4_73_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.04090.x"},{"key":"e_1_3_4_74_2","doi-asserted-by":"publisher","DOI":"10.4161\/epi.1.3.3327"},{"key":"e_1_3_4_75_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/18.11.1427"},{"key":"e_1_3_4_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2006.10.030"},{"key":"e_1_3_4_77_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.20961"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2220911120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T09:18:36Z","timestamp":1695287916000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2220911120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5]]},"references-count":77,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2023,5,9]]}},"alternative-id":["10.1073\/pnas.2220911120"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2220911120","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5]]},"assertion":[{"value":"2022-12-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2220911120"}}