LncRNAs

More than 90% of the genome is transcribed into non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). LncRNAs play important roles in regulating a wide range of cellular functions and developmental processes via function critically in the cis- and trans-regulation of gene expression, epigenetic modulation in the nucleus and post-transcriptional control in the cytoplasm. The dysregulation of lncRNAs has been linked to numerous human diseases. Our laboratory uses an RNA-centric approach to reveal the network of ncRNA-protein-genome. The long-term goal is to develop a therapeutic technology for human diseases by targeting ncRNAs.

TERRA

TElomeric Repeat containing RNA (TERRA), synthesized at the telomeric ends and highly conserved in eukaryotic cells, is a rising star lncRNA due to its crucial association with the telomere maintenance and human genetic disorders including cancer and the ICF syndrome (immunodeficiency, centromere instability, and facial anomalies). Telomeres are specialized DNA-protein structures that protect the ends of linear chromosomes and maintain genomic integrity. Studies uncovered that while TERRA plays a major role in telomere dynamics, TERRA also binds to sites throughout the genome and regulates gene expression. We are interested in the mechanisms by which TERRA regulates the telomere function and gene expression.

TERRA in Alternative Lengthening of Telomeres (ALT)

While telomerase maintains telomere length in most proliferating cells, approximately 10–15% of human cancers utilize a telomerase-independent mechanism known as Alternative Lengthening of Telomeres (ALT). ALT is driven by homologous recombination and is frequently associated with aggressive tumors and poor clinical outcomes. Despite its clinical importance, the molecular mechanisms underlying ALT remain incompletely understood, and effective targeted therapies are still lacking.

Our laboratory has uncovered a central role for TERRA in regulating the ALT pathway. We demonstrated that TERRA forms DNA:RNA hybrids (R-loops) at telomeres, which trigger telomeric DNA damage signaling and promote homologous recombination. Using our RNA-centric proteomics platform, iDRiP-MS (Identification of Direct RNA-interacting Proteins by Mass Spectrometry), we systematically identified proteins that directly interact with TERRA and discovered numerous DNA repair factors involved in ALT regulation.

Mechanistically, we showed that TERRA R-loops recruit the structure-specific endonuclease XPF to telomeres, where it generates DNA breaks that initiate DNA repair and recombination, thereby promoting telomere elongation in ALT-positive cancer cells. Importantly, depletion of XPF markedly impairs telomere maintenance and suppresses ALT cancer cell growth, identifying a promising therapeutic vulnerability for ALT-associated malignancies (Nature Communications, 2022). Our current research continues to investigate how TERRA coordinates replication stress, DNA repair, and telomere recombination, with the goal of developing novel therapeutic strategies for ALT cancers.

TERRA in Epigenetic Regulation

Our laboratory has pioneered the discovery of the epigenetic functions of TElomeric Repeat-containing RNA (TERRA), revealing that this telomeric long non-coding RNA regulates genome function far beyond chromosome ends. We demonstrated that TERRA interacts with the chromatin remodeler ATRX to maintain telomere integrity, preserve genome stability, regulate gene expression, and support early embryonic development (Cell, 2017), a study highlighted by both Cell and Nature Reviews Genetics. We further showed that TERRA binds extensively across the genome to regulate higher-order chromatin architecture and interchromosomal interactions (Nature Structural & Molecular Biology, 2017). More recently, we discovered that TERRA promotes the formation of DNA G-quadruplex (G4) structures, thereby modulating ATRX recruitment to chromatin and regulating transcription (Nucleic Acids Research, 2022). Together, these studies establish TERRA as a key epigenetic regulator that links telomere biology, chromatin organization, DNA secondary structures, and gene expression.

TERRA in Aging and Neurodegenerative Diseases

Beyond its role in telomere maintenance, TERRA is emerging as an important regulator of aging and age-related diseases. Our laboratory seeks to understand how changes in TERRA expression and function contribute to the molecular processes underlying human aging and neurodegeneration.

Using Oxford Nanopore direct RNA sequencing, we generated the first comprehensive transcriptional atlas of TERRA across all human chromosome ends, precisely defining its chromosome-specific transcriptional origins. To facilitate quantitative analysis, we also developed TERRA-QUANT, a bioinformatics pipeline that accurately measures TERRA expression from bulk and single-cell RNA sequencing datasets, providing a valuable resource for the telomere research community (Nucleic Acids Research, 2025).

By applying these technologies to large-scale transcriptomic datasets, we discovered that TERRA expression increases progressively with age across multiple human tissues, with the most prominent changes observed in blood, brain, and fibroblasts from elderly individuals. We further found that TERRA is significantly upregulated in neurons during the early stages of Alzheimer’s disease, revealing a previously unrecognized link between telomere transcription, aging, and neurodegeneration.

Our ongoing studies aim to elucidate how TERRA contributes to neuronal function, genome stability, and age-associated diseases, and to evaluate its potential as a biomarker and therapeutic target for aging and neurodegenerative disorders.