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Telomere Length and Telomerase Activity; A Yin and Yang of Cell Senescence
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Telomeric repeat-containing RNA increases in aged human cells.

Yu-Hung Hsieh1, Chin-Hua Tai1, Meng-Ting Yeh1

  • 1Institute of Molecular and Cellular Biology, National Taiwan University, No. 1 Sec. 4 Roosevelt Road, Taipei 10617, Taiwan.

Nucleic Acids Research
|July 10, 2025
PubMed
Summary
This summary is machine-generated.

Telomeric repeat-containing RNA (TERRA) sequences were fully sequenced and quantified. TERRA levels increase with age and are elevated in Alzheimer's disease, linking it to aging and neurological conditions.

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Area of Science:

  • Genomics
  • Molecular Biology
  • Epigenetics

Background:

  • Telomeric repeat-containing RNA (TERRA) is transcribed from subtelomeric regions towards telomeres.
  • Deciphering full-length TERRA sequences has been challenging.
  • TERRA's role in human aging and disease is largely unknown.

Purpose of the Study:

  • To acquire and annotate full-length TERRA sequences.
  • To develop a tool for quantifying TERRA.
  • To investigate the association of TERRA with human aging and diseases.

Main Methods:

  • TERRA-capture RNA-sequencing (RNA-seq) and Oxford Nanopore direct RNA sequencing were employed to obtain full-length TERRA.
  • The T2T-CHM13 human reference genome was used for annotation.
  • A bioinformatics tool, TERRA-QUANT, was developed for TERRA quantification from RNA-seq data.
  • Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and single-cell RNA-seq were used for validation and cell-type specific analysis.

Main Results:

  • Full-length TERRA transcripts were annotated, ranging from hundreds to over a thousand nucleotides.
  • TERRA predominantly originates from specific repeat promoters enriched with H3K4me3, RNA Pol II, CTCF, and R-loops.
  • TERRA levels were found to increase with age in blood, brain, and fibroblasts.
  • TERRA upregulation was confirmed in aged leukocytes and in neurons during human embryonic stem cell differentiation.
  • Elevated TERRA levels were observed in brain cells during the early stages of Alzheimer's disease.

Conclusions:

  • This study successfully annotated full-length TERRA transcription regions and developed a quantification tool.
  • TERRA is linked to the human aging process across multiple tissue types.
  • TERRA upregulation in aging and its association with Alzheimer's disease suggest its potential role in age-related neurological disorders.