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ALKBH3-Mediated M1A Demethylation of METTL3 Endows Pathological Fibrosis:Interplay Between M1A and M6A RNA
Liying Tu1, Shuchen Gu1, Ruoqing Xu1
1Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, P. R. China.
Abstract:
Epigenetic modifications serve as crucial molecular switches for pathological fibrosis; howbeit the role of m1A in this condition remains enigmatic. Herein, it is found that ALKBH3 exerts a pro-fibrotic effect in pathological skin fibrosis by reshaping N6-methyladenosine (m6A) RNA modification pattern. First, ALKBH3 exhibited specific upregulation within hypertrophic scars (HTS), accompanied by N1-methyladenosine (m1A) hypomethylation. Moreover, multiomics analyses identified METTL3, a critical writer enzyme involved in m6A modification, as a downstream candidate target of ALKBH3. Therapeutically, ablation of ALKBH3 inhibited the progression of HTS both in vitro and in vivo, while exogenous replenishment of METTL3 counteracted this antifibrotic effect. Mechanistically, ALKBH3 recognizes the m1A methylation sites and prevents YTHDF2-dependent mRNA decay of METTL3 transcript. Subsequently, METTL3 stabilizes collagen type I alpha 1 chain (COL1A1) and fibronectin1 (FN1) mRNAs, two major components of extracellular matrix, and therefore eliciting the pathological transformation of HTS. This observation bridges the understanding of the link between m1A and m6A methylation, the two fundamental RNA modifications, underscoring the participation of "RNA methylation crosstalk" in pathological events.
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