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Exon junction complexes regulate osteoclast-induced bone resorption by influencing the NFATc1 m6A distribution
Bao Sun1, Jin-Gang Yang2, Zhe Wang3
1Department of Oral Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai, China.
Clinical and Translational Medicine
|March 7, 2025
Summary
Exon junction complexes (EJCs) shield NFATc1 m6A methylation sites, regulating gene distribution and inhibiting osteoclast differentiation. This mechanism preserves bone mass and offers targets for osteoporosis treatment.
Area of Science:
- Molecular Biology
- Epigenetics
- Gene Regulation
Background:
- N6-methyladenosine (m6A) modification is regionally selective on the transcriptome, favoring long exons and stop codons.
- The precise mechanisms governing m6A methylation selectivity remain underexplored.
Purpose of the Study:
- To elucidate the distribution characteristics and regulatory mechanisms of m6A methylation on the NFATc1 gene.
- To investigate the role of Exon Junction Complexes (EJCs) in m6A site selectivity.
Main Methods:
- Utilized meRIP sequencing, mRNA sequencing, and luciferase reporter assays.
- Employed CRISPR/Cas9 conditional knockout mice to study NFATc1 m6A distribution.
Main Results:
- METTL14-mediated m6A methylation of NFATc1 is crucial for osteoclast differentiation and bone resorption.
- EJCs exhibit a "shield effect," protecting m6A sites within short exon fragments (50-200 nt) from hypermethylation and degradation.
- This protective effect is lost in longer exon fragments (>300 nt) or 3' UTR regions, where YTHDF2 promotes transcript degradation.
Conclusions:
- EJCs act as "shields" to dictate m6A region selectivity of the NFATc1 gene.
- EJCs regulate NFATc1 mRNA levels by influencing methylation and degradation, thereby inhibiting osteoclast differentiation and preserving bone mass.
- Findings provide insights into potential therapeutic targets for osteoporosis.
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