My research focuses on uncovering the roles and regulatory mechanisms of long non-coding RNAs (lncRNAs), particularly TERRA (Telomeric repeat-containing RNA), in epigenetic regulation, genome stability, chromatin dynamics, and telomere maintenance. I developed RNA-centric technologies—including CHIRT for mapping TERRA binding sites and iDRiP-MS for identifying RNA-binding proteins—to dissect the TERRA interactome and its genome-wide functions (Chu et al., Cell, 2017). This work revealed the role of TERRA in telomere protection, chromatin organization, and gene regulation. My lab further demonstrated that TERRA modulates DNA G-quadruplex structures and antagonizes chromatin remodeler ATRX at transcription start sites (Tsai et al., NAR, 2022), unveiling an RNA-based mechanism for epigenetic regulation. We also elucidated how TERRA contributes to Alternative Lengthening of Telomeres (ALT) in cancer by forming R-loops that recruit DNA repair proteins like XPF to initiate telomere synthesis (Guh et al., Nat Commun, 2022). Recently, we applied nanopore direct RNA-seq to characterize the TERRA transcriptome in human tissues, revealing increased TERRA levels during aging and early Alzheimer’s disease, suggesting TERRA as a potential biomarker for age-related disorders (Hsieh et al., NAR, 2025). Collectively, our research bridges RNA biology, telomere dynamics, and genome integrity, offering novel insights into non-coding RNA functions in both development and disease. In this meeting, I will present our recent findings on how TERRA is involved in ALT cancer, aging, and human diseases.