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

Mužina, Karolina (avtor), Markež, Ana (avtor), Jenko Bizjan, Barbara (avtor), Šamec, Neja (avtor), Kovač, Jernej (avtor), Dovč, Klemen (avtor), Battelino, Tadej (avtor), Pokorn, Marko (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: RNA-seq, autoimmune disease, autoimmunity, epigenetic, methylation, sequencing, transposable elements
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.02 - Pregledni znanstveni članek
• Organizacija: MF - Medicinska fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2026
• Št. strani: 19 str.
• Številčenje: Vol. 17, art. 1774863
• PID: 20.500.12556/RUL-186238
• UDK: 61:575
• ISSN pri članku: 1664-3224
• DOI: 10.3389/fimmu.2026.1774863
• COBISS.SI-ID: 288321795
• Datum objave v RUL: 28.08.2026

Gradivo je del revije

• Naslov: Frontiers in immunology
• Skrajšan naslov: Front. immunol.
• Založnik: Frontiers Media
• ISSN: 1664-3224
• COBISS.SI-ID: 30774233

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.