{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T06:33:57Z","timestamp":1789194837427,"version":"build-2803163510"},"posted":{"date-parts":[[2025,7,17]]},"group-title":"Genomics","reference-count":72,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["R35 GM142395"],"award-info":[{"award-number":["R35 GM142395"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Science Foundation","award":["DGE-1842487"],"award-info":[{"award-number":["DGE-1842487"]}]},{"award":["T32 AG052374"],"award-info":[{"award-number":["T32 AG052374"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30 AG068345"],"award-info":[{"award-number":["P30 AG068345"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Office of the Director","award":["S10 OD028654"],"award-info":[{"award-number":["S10 OD028654"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  During aging and cellular senescence, repetitive elements are frequently transcriptionally derepressed across species and cell types. Among these, the most abundant repeats by copy number in the human genome are\n                  <jats:italic>Alu<\/jats:italic>\n                  retrotransposons. Though\n                  <jats:italic>Alu<\/jats:italic>\n                  elements are often studied for their mutagenic potential, there is increasing appreciation for their contributions to other biological functions, including pro-inflammatory signaling and mitochondrial dysfunction. However, a comprehensive analysis of\n                  <jats:italic>Alu<\/jats:italic>\n                  -driven molecular changes remains to be conducted, and\n                  <jats:italic>Alu<\/jats:italic>\n                  \u2019s potential contributions to aging features remain incompletely characterized. Here, we show that overexpression of an\n                  <jats:italic>AluJb<\/jats:italic>\n                  transposon in human primary IMR-90 fibroblasts leads to large-scale alterations across the transcriptome, cellular proteome, and secretome. Functional genomics analyses reveal alterations in aging pathways, broadly, and mitochondrial metabolism, proteostasis, cell cycle, and extracellular matrix pathways, more specifically. Our results demonstrate that\n                  <jats:italic>Alu<\/jats:italic>\n                  transcriptional upregulation is sufficient to drive widespread disruptions to cellular homeostasis that mirror aging-associated alterations.\n                <\/jats:p>","DOI":"10.1101\/2025.07.11.664466","type":"posted-content","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T20:01:46Z","timestamp":1752782506000},"source":"Crossref","is-referenced-by-count":1,"title":["A multi-omics analysis of human fibroblasts overexpressing an\n                  <i>Alu<\/i>\n                  transposon reveals widespread disruptions in aging-associated pathways"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9429-0488","authenticated-orcid":false,"given":"Juan I.","family":"Bravo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6073-3711","authenticated-orcid":false,"given":"Eyael","family":"Tewelde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina D.","family":"King","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Bons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samah","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Rose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6858-9462","authenticated-orcid":false,"given":"Judith","family":"Campisi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9907-2749","authenticated-orcid":false,"given":"Birgit","family":"Schilling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7401-4777","authenticated-orcid":false,"given":"B\u00e9r\u00e9nice A.","family":"Benayoun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025101705350715000_2025.07.11.664466v2.1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1016072014259"},{"key":"2025101705350715000_2025.07.11.664466v2.2","doi-asserted-by":"crossref","unstructured":"Bravo, J.I. , et al., Transposable elements, circular RNAs and mitochondrial transcription in age-related genomic regulation. Development, 2020. 147(11).","DOI":"10.1242\/dev.175786"},{"key":"2025101705350715000_2025.07.11.664466v2.3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002591"},{"key":"2025101705350715000_2025.07.11.664466v2.4","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12465"},{"key":"2025101705350715000_2025.07.11.664466v2.5","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3368"},{"key":"2025101705350715000_2025.07.11.664466v2.6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1604621113"},{"issue":"12","key":"2025101705350715000_2025.07.11.664466v2.7","first-page":"867","article-title":"Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues","volume":"5","year":"2013","journal-title":"Aging (Albany NY"},{"key":"2025101705350715000_2025.07.11.664466v2.8","doi-asserted-by":"publisher","DOI":"10.1101\/gr.240093.118"},{"key":"2025101705350715000_2025.07.11.664466v2.9","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12047"},{"key":"2025101705350715000_2025.07.11.664466v2.10","doi-asserted-by":"publisher","DOI":"10.4161\/cc.10.17.17543"},{"key":"2025101705350715000_2025.07.11.664466v2.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0784-9"},{"key":"2025101705350715000_2025.07.11.664466v2.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2014.01.007"},{"key":"2025101705350715000_2025.07.11.664466v2.13","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2017.369"},{"key":"2025101705350715000_2025.07.11.664466v2.14","doi-asserted-by":"crossref","unstructured":"Luca, C.D. , et al., Enhanced expression of LINE-1-encoded ORF2 protein in early stages of colon and prostate transformation. Oncotarget, 2015. 7(4).","DOI":"10.18632\/oncotarget.6767"},{"key":"2025101705350715000_2025.07.11.664466v2.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.05.020"},{"issue":"10","key":"2025101705350715000_2025.07.11.664466v2.16","doi-asserted-by":"crossref","first-page":"2874","DOI":"10.1016\/j.celrep.2018.05.004","article-title":"Tau Activates Transposable Elements in Alzheimer&#x2019;s Disease","volume":"23","year":"2018","journal-title":"Cell Reports"},{"key":"2025101705350715000_2025.07.11.664466v2.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0194-1"},{"key":"2025101705350715000_2025.07.11.664466v2.18","doi-asserted-by":"publisher","DOI":"10.1038\/35057062"},{"key":"2025101705350715000_2025.07.11.664466v2.19","doi-asserted-by":"publisher","DOI":"10.1126\/science.1058040"},{"key":"2025101705350715000_2025.07.11.664466v2.20","doi-asserted-by":"publisher","DOI":"10.1038\/284372a0"},{"key":"2025101705350715000_2025.07.11.664466v2.21","doi-asserted-by":"publisher","DOI":"10.1038\/ng1223"},{"key":"2025101705350715000_2025.07.11.664466v2.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2008.04.007"},{"key":"2025101705350715000_2025.07.11.664466v2.23","doi-asserted-by":"publisher","DOI":"10.1101\/gr.081737.108"},{"key":"2025101705350715000_2025.07.11.664466v2.24","doi-asserted-by":"publisher","DOI":"10.1038\/312171a0"},{"issue":"11","key":"2025101705350715000_2025.07.11.664466v2.25","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1016\/j.bbamcr.2013.02.021","article-title":"Co-translational targeting and translocation of proteins to the endoplasmic reticulum","volume":"1833","year":"2013","journal-title":"Biochimica et Biophysica Acta (BBA) - Molecular Cell Research"},{"key":"2025101705350715000_2025.07.11.664466v2.26","doi-asserted-by":"publisher","DOI":"10.1038\/299691a0"},{"key":"2025101705350715000_2025.07.11.664466v2.27","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-440X(02)00292-0"},{"issue":"1","key":"2025101705350715000_2025.07.11.664466v2.28","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1038\/s41467-025-56351-6","article-title":"7SL RNA and signal recognition particle orchestrate a global cellular response to acute thermal stress","volume":"16","year":"2025","journal-title":"Nature Communications"},{"key":"2025101705350715000_2025.07.11.664466v2.29","doi-asserted-by":"publisher","DOI":"10.1186\/s13100-015-0041-9"},{"key":"2025101705350715000_2025.07.11.664466v2.30","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.omtn.2017.11.006","article-title":"Delineation of the Exact Transcription Termination Signal for Type 3 Polymerase III","volume":"10","year":"2018","journal-title":"Molecular Therapy - Nucleic Acids"},{"issue":"2","key":"2025101705350715000_2025.07.11.664466v2.31","doi-asserted-by":"crossref","first-page":"e32","DOI":"10.1002\/cpz1.32","article-title":"Quantitative Proteomic Analysis of the Senescence-Associated Secretory Phenotype by Data-Independent Acquisition","volume":"1","year":"2021","journal-title":"Current Protocols"},{"key":"2025101705350715000_2025.07.11.664466v2.32","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201100463"},{"issue":"6","key":"2025101705350715000_2025.07.11.664466v2.33","first-page":"O111.016717-O111.016717","article-title":"Targeted data extraction of the MS\/MS spectra generated by data-independent acquisition: a new concept for consistent and accurate proteome analysis","volume":"11","year":"2012","journal-title":"Molecular & cellular proteomics : MCP"},{"issue":"12","key":"2025101705350715000_2025.07.11.664466v2.34","doi-asserted-by":"crossref","first-page":"2296","DOI":"10.1074\/mcp.RA117.000314","article-title":"Optimization of Experimental Parameters in Data-Independent Mass Spectrometry Significantly Increases Depth and Reproducibility of Results","volume":"16","year":"2017","journal-title":"Molecular & cellular proteomics : MCP"},{"issue":"1","key":"2025101705350715000_2025.07.11.664466v2.35","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/s41467-017-00249-5","article-title":"Multi-laboratory assessment of reproducibility, qualitative and quantitative performance of SWATH-mass spectrometry","volume":"8","year":"2017","journal-title":"Nature communications"},{"key":"2025101705350715000_2025.07.11.664466v2.36","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty560"},{"key":"2025101705350715000_2025.07.11.664466v2.37","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky955.30357393"},{"key":"2025101705350715000_2025.07.11.664466v2.38","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2025101705350715000_2025.07.11.664466v2.39","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv422"},{"key":"2025101705350715000_2025.07.11.664466v2.40","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"issue":"1","key":"2025101705350715000_2025.07.11.664466v2.41","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1186\/s13059-018-1599-6","article-title":"Predicting age from the transcriptome of human dermal fibroblasts","volume":"19","year":"2018","journal-title":"Genome Biology"},{"key":"2025101705350715000_2025.07.11.664466v2.42","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13167"},{"key":"2025101705350715000_2025.07.11.664466v2.43","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.87811.3"},{"issue":"6","key":"2025101705350715000_2025.07.11.664466v2.44","doi-asserted-by":"crossref","first-page":"e1011311","DOI":"10.1371\/journal.pgen.1011311","article-title":"An eQTL-based approach reveals candidate regulators of LINE-1 RNA levels in lymphoblastoid cells","volume":"20","year":"2024","journal-title":"PLOS Genetics"},{"key":"2025101705350715000_2025.07.11.664466v2.45","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"2025101705350715000_2025.07.11.664466v2.46","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.7b00170"},{"issue":"3","key":"2025101705350715000_2025.07.11.664466v2.47","doi-asserted-by":"crossref","first-page":"100141","DOI":"10.1016\/j.xinn.2021.100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","year":"2021","journal-title":"The Innovation"},{"key":"2025101705350715000_2025.07.11.664466v2.48","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-020-06856-9"},{"key":"2025101705350715000_2025.07.11.664466v2.49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"issue":"6","key":"2025101705350715000_2025.07.11.664466v2.50","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","year":"2015","journal-title":"Cell Syst"},{"issue":"D1","key":"2025101705350715000_2025.07.11.664466v2.51","first-page":"D672","article-title":"The Reactome Pathway Knowledgebase 2024","volume":"52","year":"2023","journal-title":"Nucleic Acids Research"},{"key":"2025101705350715000_2025.07.11.664466v2.52","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000599"},{"issue":"1","key":"2025101705350715000_2025.07.11.664466v2.53","doi-asserted-by":"crossref","first-page":"4827","DOI":"10.1038\/s41467-022-32552-1","article-title":"A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues","volume":"13","year":"2022","journal-title":"Nature Communications"},{"key":"2025101705350715000_2025.07.11.664466v2.54","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-01990-9"},{"issue":"1","key":"2025101705350715000_2025.07.11.664466v2.55","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41420-018-0093-y","article-title":"An analysis of aging-related genes derived from the Genotype-Tissue Expression project (GTEx)","volume":"4","year":"2018","journal-title":"Cell Death Discovery"},{"key":"2025101705350715000_2025.07.11.664466v2.56","doi-asserted-by":"crossref","unstructured":"Cantarella, S. , et al., Alu RNA Modulates the Expression of Cell Cycle Genes in Human Fibroblasts. Int J Mol Sci, 2019. 20(13).","DOI":"10.3390\/ijms20133315"},{"key":"2025101705350715000_2025.07.11.664466v2.57","doi-asserted-by":"crossref","unstructured":"Badia-i-Mompel, P. , et al., decoupleR: ensemble of computational methods to infer biological activities from omics data. Bioinformatics Advances, 2022. 2(1).","DOI":"10.1093\/bioadv\/vbac016"},{"key":"2025101705350715000_2025.07.11.664466v2.58","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad841"},{"key":"2025101705350715000_2025.07.11.664466v2.59","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz240"},{"issue":"6","key":"2025101705350715000_2025.07.11.664466v2.60","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/nprot.2015.052","article-title":"NetworkAnalyst for statistical, visual and network-based meta-analysis of gene expression data","volume":"10","year":"2015","journal-title":"Nature Protocols"},{"key":"2025101705350715000_2025.07.11.664466v2.61","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku443"},{"key":"2025101705350715000_2025.07.11.664466v2.62","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-40204-4_3"},{"issue":"1","key":"2025101705350715000_2025.07.11.664466v2.63","doi-asserted-by":"crossref","first-page":"2793","DOI":"10.1038\/s41467-022-30484-4","article-title":"PRRX1 is a master transcription factor of stromal fibroblasts for myofibroblastic lineage progression","volume":"13","year":"2022","journal-title":"Nature Communications"},{"key":"2025101705350715000_2025.07.11.664466v2.64","doi-asserted-by":"publisher","DOI":"10.2337\/db20-0619"},{"issue":"1","key":"2025101705350715000_2025.07.11.664466v2.65","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.3390\/cancers3011383","article-title":"Epigenetic Regulation by Lysine Demethylase 5 (KDM5) Enzymes in Cancer","volume":"3","year":"2011","journal-title":"Cancers (Basel"},{"key":"2025101705350715000_2025.07.11.664466v2.66","doi-asserted-by":"crossref","unstructured":"Kiuchi, M. , et al., The Cxxc1 subunit of the Trithorax complex directs epigenetic licensing of CD4+ T cell differentiation. J Exp Med, 2021. 218(4).","DOI":"10.1084\/jem.20201690"},{"key":"2025101705350715000_2025.07.11.664466v2.67","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.03.011"},{"issue":"2","key":"2025101705350715000_2025.07.11.664466v2.68","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/s41594-020-0372-1","article-title":"Cell fitness screens reveal a conflict between LINE-1 retrotransposition and DNA replication","volume":"27","year":"2020","journal-title":"Nature structural & molecular biology"},{"key":"2025101705350715000_2025.07.11.664466v2.69","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3185"},{"key":"2025101705350715000_2025.07.11.664466v2.70","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4450"},{"issue":"8","key":"2025101705350715000_2025.07.11.664466v2.71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1167\/tvst.9.8.1","article-title":"Lamivudine Inhibits Alu RNA-induced Retinal Pigment Epithelium Degeneration via Anti-inflammatory and Anti-senescence Activities","volume":"9","year":"2020","journal-title":"Translational Vision Science & Technology"},{"key":"2025101705350715000_2025.07.11.664466v2.72","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-019-02082-w"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.07.11.664466","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:00:36Z","timestamp":1782277236000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.07.11.664466"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,17]]},"references-count":72,"URL":"https:\/\/doi.org\/10.1101\/2025.07.11.664466","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1007\/s11357-025-02033-6","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,7,17]]},"subtype":"preprint"}}