Telomeric Repeat-Containing lncRNA TERRA Targets Non-Telomeric DNA in Trans via R-Loops

Telomeres are transcribed into telomeric repeat-containing RNA (TERRA), a long non-coding RNA known to play key roles in telomere maintenance and DNA repair. While TERRA’s formation of R-loops at telomeric regions is well documented, its interaction with non-telomeric DNA remains poorly understood. In this study, we reanalyzed publicly available datasets using bioinformatic approaches and found evidence that TERRA binds non-telomeric DNA regions in trans through R-loop formation. Notably, the presence of tandem telomeric repeat motifs within non-telomeric regions enhanced TERRA binding, suggesting sequence-dependent R-loop formation. Furthermore, analysis of previously identified TERRA-regulated genes revealed that such distal TERRA-DNA interactions may influence telomere elongation by modulating the expression of telomere maintenance factors. These findings provide new insights into the broader regulatory functions of TERRA beyond telomeres and suggest a potential mechanism for its role in genome-wide gene regulation via R-loops.