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METTL14 Regulates Intestine Cellular Senescence through m6A Modification of Lamin B Receptor

Zizhen Zhang1,2,3, Meng Xue1,2,3, Jingyu Chen1,2

  • 1Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang, China.

Oxidative Medicine and Cellular Longevity
|December 29, 2022
PubMed

Insights

N-6-Methyladenosine (m6A) methyltransferase-like 14 (METTL14) decreases with age, impacting intestinal integrity and lifespan. METTL14 regulates lamin B receptor (LBR) mRNA stability, preventing cellular senescence.

Area of Science:

  • Molecular Biology
  • Aging Research
  • Epigenetics

Background:

  • N-6-Methyladenosine (m6A) modification is crucial for biological processes, including aging.
  • The specific role of m6A methyltransferase-like 14 (METTL14) in the aging process is not well understood.

Purpose of the Study:

  • To investigate the regulation of METTL14 in aging.
  • To elucidate the molecular mechanisms by which METTL14 influences aging and cellular senescence.

Main Methods:

  • Comparative analysis of m6A levels and METTL14 expression in young versus aged mice intestines.
  • Genetic manipulation (knockdown and overexpression) of Mettl14 in *Drosophila melanogaster* and human CCD-18Co cells.
  • Assessment of lifespan, intestinal integrity, climbing ability, and cellular senescence phenotypes.
  • Identification and validation of METTL14 target genes using m6A sequencing and mRNA stability assays.

Main Results:

  • METTL14 expression and m6A modification levels were significantly reduced in aged mice intestines compared to young mice.
  • Mettl14 knockdown in *Drosophila* led to shortened lifespan, impaired intestinal integrity, and reduced mobility.
  • METTL14 depletion in human cells accelerated cellular senescence, while its overexpression rescued these phenotypes.
  • Lamin B receptor (LBR) was identified as a direct target of METTL14, with reduced m6A modification leading to LBR mRNA instability and subsequent senescence.

Conclusions:

  • METTL14 plays a critical role in regulating the aging process through m6A modification.
  • METTL14-mediated regulation of LBR mRNA stability is a key mechanism driving cellular senescence.
  • METTL14 represents a potential therapeutic target for interventions against age-related decline and cellular senescence.

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