20.500.12556/DiRROS-31961 Transposable elements as a possible missing link between genetic predisposition and environmental triggers of autoimmune disorders insights from type 1 diabetes, systemic lupus erythematosus and rheumatoid arthritis Transposable elements (TEs) make up almost half of the human genome and are among its most densely methylated regions. Their epigenetic silencing is crucial for genomic stability and immune homeostasis, and accumulating evidence indicates that dysregulated TE methylation and expression contribute to autoimmune disease pathogenesis. Hypomethylation of selected TE families can permit transcriptional reactivation, production of immunostimulatory nucleic acids and peptides, and engagement of pattern-recognition receptors, thereby driving type I interferon (IFN-I) signaling through “viral mimicry”–like mechanisms. In parallel, TE-derived enhancers, promoters and exons reshape gene regulatory networks at immune loci. In this narrative review, we synthesize current knowledge on TE methylation and expression in autoimmunity, with a focus on type 1 diabetes (T1D), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). We first outline TE biology and the principal mechanisms of epigenetic silencing, then summarise methodological advances for TE methylation and expression profiling, including long-read sequencing and TE-aware RNA-seq pipelines. We next dissect disease-specific evidence: longitudinal epigenomic studies in T1D showing preclinical DNA methylation changes and altered Alu/LINE-1 patterns, together with HERV-H/W upregulation at onset, SLE studies demonstrating LINE-1 hypomethylation in neutrophils and cell-type–specific TE overexpression that tracks with IFN signatures and nucleic acid sensor pathways, and RA studies linking global and LINE-1 methylation to methotrexate response when integrated with serostatus. Across conditions, TE methylation behaves more like a relatively stable disease-associated trait than a simple activity marker and exhibits clear disease- and cell-type-specific signatures rather than global hypomethylation. We conclude that TEs are not passive genomic relics but epigenetically regulated elements that can act as endogenous sources of immunostimulatory nucleic acids, neoantigens and regulatory sequences, providing a mechanistic bridge between genetic susceptibility and environmental triggers in autoimmunity. Consequently, selective dysregulation of TE methylation and expression offers both an explanatory framework for interferon-driven autoimmunity and a promising, currently underused layer for biomarker development and therapeutic targeting. RNA-seq autoimmune disease autoimmunity epigenetic methylation sequencing transposable elements true false true Angleški jezik Ni določen Neznano 2026-08-20 12:19:42 2026-08-20 12:19:43 2026-08-22 03:47:30 0000-00-00 00:00:00 2026 0 0 Nasl. z nasl. zaslona; Opis vira z dne 20. 8. 2026; str. 1-19 [article no.] 1774863 Vol. 17 2026 0000-00-00 Zaloznikova Objavljeno apc 0000-00-00 0000-00-00 0000-00-00 61:575 1664-3224 10.3389/fimmu.2026.1774863 288321795 RAZ_Muzina_Karolina_2026.pdf RAZ_Muzina_Karolina_2026.pdf 1 9305FDC3E136FAF46C65554CA2834F71 8175ab7a7d26b4adb0c2324a9191849e741dcbe38a90736faa98bcb15b384a11 d36141ee-9c80-11f1-af5a-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=49760 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1774863/full 1 ac2ee4de-9c80-11f1-af5a-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=49759 Univerzitetni klinični center Ljubljana 0 0 0