{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T23:43:00Z","timestamp":1792885380310,"version":"4.5.0"},"reference-count":69,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"657","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2022,8,10]]},"abstract":"<jats:p>\n                    Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. During physiological and pathological premature aging, heterochromatin homeostasis is profoundly compromised. Here, we showed that\n                    <jats:italic>LINE-1<\/jats:italic>\n                    (\n                    <jats:italic>Long Interspersed Nuclear Element-1; L1<\/jats:italic>\n                    ) RNA accumulation was an early event in both typical and atypical human progeroid syndromes.\n                    <jats:italic>L1<\/jats:italic>\n                    RNA negatively regulated the enzymatic activity of the histone-lysine\n                    <jats:italic>N<\/jats:italic>\n                    -methyltransferase SUV39H1 (suppression of variegation 3-9 homolog 1), resulting in heterochromatin loss and onset of senescent phenotypes in vitro. Depletion of\n                    <jats:italic>L1<\/jats:italic>\n                    RNA in dermal fibroblast cells from patients with different progeroid syndromes using specific antisense oligonucleotides (ASOs) restored heterochromatin histone 3 lysine 9 and histone 3 lysine 27 trimethylation marks, reversed DNA methylation age, and counteracted the expression of senescence-associated secretory phenotype genes such as\n                    <jats:italic>p16<\/jats:italic>\n                    ,\n                    <jats:italic>p21<\/jats:italic>\n                    ,\n                    <jats:italic>activating transcription factor 3<\/jats:italic>\n                    (\n                    <jats:italic>ATF3<\/jats:italic>\n                    ),\n                    <jats:italic>matrix metallopeptidase 13<\/jats:italic>\n                    (\n                    <jats:italic>MMP13<\/jats:italic>\n                    ),\n                    <jats:italic>interleukin 1a<\/jats:italic>\n                    (\n                    <jats:italic>IL1a<\/jats:italic>\n                    ),\n                    <jats:italic>BTG anti-proliferation factor 2<\/jats:italic>\n                    (\n                    <jats:italic>BTG2<\/jats:italic>\n                    ), and\n                    <jats:italic>growth arrest and DNA damage inducible beta<\/jats:italic>\n                    (\n                    <jats:italic>GADD45b<\/jats:italic>\n                    ). Moreover, systemic delivery of ASOs rescued the histophysiology of tissues and increased the life span of a Hutchinson-Gilford progeria syndrome mouse model. Transcriptional profiling of human and mouse samples after\n                    <jats:italic>L1<\/jats:italic>\n                    RNA depletion demonstrated that pathways associated with nuclear chromatin organization, cell proliferation, and transcription regulation were enriched. Similarly, pathways associated with aging, inflammatory response, innate immune response, and DNA damage were down-regulated. Our results highlight the role of\n                    <jats:italic>L1<\/jats:italic>\n                    RNA in heterochromatin homeostasis in progeroid syndromes and identify a possible therapeutic approach to treat premature aging and related syndromes.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.abl6057","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T13:58:13Z","timestamp":1660139893000},"source":"Crossref","is-referenced-by-count":134,"title":["<i>LINE-1<\/i>\n                    RNA causes heterochromatin erosion and is a target for amelioration of senescent phenotypes in progeroid syndromes"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9889-1283","authenticated-orcid":true,"given":"Francesco","family":"Della Valle","sequence":"first","affiliation":[{"name":"King Abdullah University of Science and Technology (KAUST), Biological Environmental Sciences and Engineering Division BESE, KAUST Environmental Epigenetics Program, Thuwal, Saudi Arabia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9173-3845","authenticated-orcid":true,"given":"Pradeep","family":"Reddy","sequence":"additional","affiliation":[{"name":"Salk Institute for Biological Studies, La Jolla, CA, USA."},{"name":"Altos Labs, San Diego, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mako","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Salk Institute for Biological Studies, La Jolla, CA, USA."},{"name":"Altos Labs, San Diego, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5490-7343","authenticated-orcid":true,"given":"Peng","family":"Liu","sequence":"additional","affiliation":[{"name":"King Abdullah University of Science and Technology (KAUST), Biological Environmental Sciences and Engineering Division BESE, KAUST Environmental Epigenetics Program, Thuwal, Saudi Arabia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0106-2353","authenticated-orcid":true,"given":"Alfonso","family":"Saera-Vila","sequence":"additional","affiliation":[{"name":"Sequentia Biotech, Carrer Comte D\u2019Urgell 240, Barcelona 08036, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalila","family":"Bensaddek","sequence":"additional","affiliation":[{"name":"King Abdullah University of Science and Technology (KAUST), Bioscience Core Lab,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5416-0358","authenticated-orcid":true,"given":"Huoming","family":"Zhang","sequence":"additional","affiliation":[{"name":"King Abdullah University of Science and Technology (KAUST), Bioscience Core Lab,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Prieto Martinez","sequence":"additional","affiliation":[{"name":"Salk Institute for Biological Studies, La Jolla, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Abassi","sequence":"additional","affiliation":[{"name":"King Abdullah University of Science and Technology (KAUST), Biological Environmental Sciences and Engineering Division BESE, KAUST Environmental Epigenetics Program, Thuwal, Saudi Arabia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirko","family":"Celii","sequence":"additional","affiliation":[{"name":"King Abdullah University of Science and Technology (KAUST), Biological Environmental Sciences and Engineering Division BESE, KAUST Environmental Epigenetics Program, Thuwal, Saudi Arabia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Ocampo","sequence":"additional","affiliation":[{"name":"Salk Institute for Biological Studies, La Jolla, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0554-2365","authenticated-orcid":true,"given":"Estrella","family":"Nu\u00f1ez Delicado","sequence":"additional","affiliation":[{"name":"Thuwal, Saudi Arabia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9551-9344","authenticated-orcid":true,"given":"Arianna","family":"Mangiavacchi","sequence":"additional","affiliation":[{"name":"King Abdullah University of Science and Technology (KAUST), Biological Environmental Sciences and Engineering Division BESE, KAUST Environmental Epigenetics Program, Thuwal, Saudi Arabia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9058-6994","authenticated-orcid":true,"given":"Riccardo","family":"Aiese Cigliano","sequence":"additional","affiliation":[{"name":"Sequentia Biotech, Carrer Comte D\u2019Urgell 240, Barcelona 08036, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Concepcion","family":"Rodriguez Esteban","sequence":"additional","affiliation":[{"name":"Salk Institute for Biological Studies, La Jolla, CA, USA."},{"name":"Altos Labs, San Diego, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Horvath","sequence":"additional","affiliation":[{"name":"Altos Labs, San Diego, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0557-8875","authenticated-orcid":true,"given":"Juan Carlos","family":"Izpisua Belmonte","sequence":"additional","affiliation":[{"name":"Salk Institute for Biological Studies, La Jolla, CA, USA."},{"name":"Altos Labs, San Diego, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4906-8511","authenticated-orcid":true,"given":"Valerio","family":"Orlando","sequence":"additional","affiliation":[{"name":"King Abdullah 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