A team at Shanghai East Hospital (Tongji University) finds that transcription factor ELF1 binds promoters of METTL3 and YTHDF2 to increase m6A methylation on E2F3 mRNA, triggering its degradation. This epigenetic mechanism accelerates nucleus pulposus cell senescence and intervertebral disc degeneration, pointing to novel targets for anti‐aging spinal therapies.
Key points
ELF1 binds METTL3 and YTHDF2 promoters to upregulate m6A writer and reader in nucleus pulposus cells.
METTL3 installs m6A marks on E2F3 mRNA, and YTHDF2 recognizes these sites, accelerating mRNA decay.
In Elf1 knockout mice, reduced m6A and preserved E2F3 delay nucleus pulposus cell senescence and disc degeneration.
Why it matters:
By revealing a specific ELF1-driven m6A epigenetic circuit that hastens disc cell aging, this work identifies actionable molecular targets for therapies to delay spinal degeneration.
Q&A
What is m6A RNA methylation?
How does ELF1 regulate METTL3 and YTHDF2?
Why is E2F3 important for cell aging?
What models were used to study disc cell senescence?
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Academy
Understanding m6A RNA Modification
What is m6A? N6-methyladenosine (m6A) is a common chemical modification on messenger RNA (mRNA). It involves adding a methyl group to the nitrogen at position 6 of adenosine bases within RNA strands. This modification influences how RNA molecules fold, are processed, and are translated into proteins.
Key Players:
- Writers (e.g., METTL3/METTL14): Enzymes that install m6A marks.
- Erasers (e.g., FTO, ALKBH5): Enzymes that remove m6A marks.
- Readers (e.g., YTHDF2): Proteins that bind m6A-tagged RNA and influence its fate.
How m6A Controls RNA Fate
- Stability: m6A can speed up or slow down RNA degradation, altering how long messages stick around.
- Translation: m6A may enhance or reduce the efficiency by which ribosomes make proteins from RNA.
- Splicing & Processing: m6A marks guide how precursor RNAs are spliced and matured.
m6A in Aging and Longevity Science
During aging, cells accumulate damage and undergo senescence, halting division. Epigenetic changes, including shifts in m6A levels, play a central role in this process. Aberrant m6A patterns can disrupt the expression of key cell cycle regulators, forcing cells into a senescent state and contributing to age-related tissue decline.
Implications for Longevity:
- Monitoring m6A levels may serve as a biomarker for biological aging.
- Targeting m6A writers or readers could delay cell senescence and extend tissue function.
- Small-molecule inhibitors or genetic interventions that modulate m6A enzymes are emerging as potential anti-aging therapies.
METTL3 and YTHDF2: Drivers of Senescence
METTL3 installs m6A tags on transcripts that regulate the cell cycle. Increased METTL3 activity can accelerate mRNA decay of crucial genes, pushing cells toward senescence.
YTHDF2 reads m6A marks, binding modified RNA and recruiting decay complexes. Upregulation of YTHDF2 further enhances degradation of cell cycle mRNAs.
Together, the METTL3–YTHDF2 axis reshapes the transcriptome during aging, making it a prime target for therapies aimed at preserving cell function.
