A groundbreaking study conducted by a research team from National Taiwan University, Academia Sinica, and National Taiwan University Hospital has shed light on a significant link between a specific RNA molecule and the process of human aging, as well as early-stage Alzheimer’s disease. Their findings, recently published in the prestigious journal Nucleic Acids Research, highlight TERRA—a long non-coding RNA that is transcribed from the ends of chromosomes—as a potential biomarker for age-related conditions and neurodegenerative diseases.
TERRA, also known as Telomeric Repeat-Containing RNA, is derived from the telomeres at the ends of chromosomes and comprises repetitive UUAGGG sequences along with unique subtelomeric sequences specific to each chromosome. While the role of TERRA in telomere biology is well-established, its precise involvement in human aging has remained elusive until now.
In order to overcome the technical challenges associated with studying TERRA, such as its repetitive nature and unassembled genomic regions, the research team utilized Oxford Nanopore direct RNA sequencing along with the recently completed T2T-CHM13 human genome reference. By enriching TERRA transcripts and mapping their locations, they were able to generate the first comprehensive annotation of TERRA transcription regions across all chromosome ends.
The researchers also developed a novel computational tool called TERRA-QUANT, which enables robust analysis of TERRA levels from various RNA-seq datasets, including bulk tissue and single-cell data. Leveraging this tool, they analyzed extensive RNA sequencing datasets from human tissues spanning different age groups.
Some key discoveries from the study include:
– A significant increase in TERRA levels with age in human blood, brain, and fibroblast tissues.
– Dysregulated expression of TERRA in fibroblasts from patients with Hutchinson-Gilford Progeria Syndrome (HGPS), a rare genetic disorder characterized by premature aging.
– Elevated TERRA expression in neurons derived from embryonic stem cells and during the early stages of Alzheimer’s disease, as revealed by single-cell data.
The team validated their findings using RT-qPCR, confirming the upregulation of TERRA in aged blood cells and neurons derived from individuals with Alzheimer’s disease. Dr. Hsueh-Ping Catherine Chu, the lead investigator of the study, remarked, “These results suggest that TERRA not only serves as a marker of cellular aging but may also play a functional role in age-related diseases.”
This groundbreaking study marks the first demonstration of the association between TERRA expression and aging, as well as early neurodegeneration in humans. It paves the way for further exploration of how TERRA could be utilized to comprehend and potentially monitor age-related conditions.
For more information, the study titled “Telomeric repeat-containing RNA increases in aged human cells” can be accessed in Nucleic Acids Research.
This research was made possible by the collaborative efforts of National Taiwan University, providing valuable insights into the intricate relationship between TERRA and human aging and neurodegenerative disorders.
