METTL3 regulates inflammatory pain by modulating m ⁶ A‐dependent pri‐miR‐365‐3p processing

Abstract

N6‐methyladenosine (m6A) modification in RNA has been implicated in diverse biological processes. However, very little is currently known about its role in nociceptive modulation. Here, we found that the level of spinal m6A modification was significantly increased in a mouse model of Complete Freund's Adjuvant (CFA)‐induced chronic inflammatory pain, which was accompanied with the augmentation of methyltransferase‐like 3 (METTL3) expression in the spinal cord. Knockdown of spinal METTL3 prevented and reversed CFA‐induced pain behaviors and spinal neuronal sensitization. In contrast, overexpression of spinal METTL3 produced pain behaviors and neuronal sensitization in naive mice. Moreover, we found that METTL3 positively modulated the pri‐miR‐65‐3p processing in a microprocessor protein DiGeorge critical region 8‐dependent manner. Collectively, our findings reveal an important role of METTL3‐mediated m6A modification in nociceptive sensitization and provide a novel perspective on m6A modification in the development of pathological pain.

Mettl14-mediated m6A modification modulates neuron apoptosis during the repair of spinal cord injury by regulating the transformation from pri‐mir‐375 to miR-375

“…m6A modification is critical for neuronal processes and disorders, and learning and memory [28,29]. Mettl14 and m6A levels were upregulated in breast cancer tissues [12].…”

“…In this study, the content of m6A in total RNA and Mettl14 levels of SCI rats were significantly increased. Similarly, level of spinal m6A modification was clearly increased in a mouse model of chronic inflammatory pain, with the augmented Mettl3 in the spinal cord [29]. Given that levels of Mettl14 and m6A are increased in the spinal cord and that Mettl14 is important in mediating m6A formation, we considered whether intervention of Mettl14 could affect SCI in a m6A modification-dependent manner.…”

Biological functions of m6A methyltransferases

“…Recent work on inflammation has yielded some intriguing mechanistic insights into how it might be affected by m 6 A methyltransferases. METTL3 fostered pri-miR-65-3p processing in a microprocessor protein DiGeorge critical region 8-dependent manner to induce inflammatory pain and neuronal sensitization [110]. It also suppressed the expression of MyD88S, which inhibited inflammatory cytokine production, and then promoted the expression of inflammatory cytokines in LPS-induced human dental pulp cells (HDPCs), as well as related markers in the NF-κB and MAPK signalling pathways [111].…”

The Emerging Clinical Application of m6A RNA Modification in Inflammatory Bowel Disease and Its Associated Colorectal Cancer

“…This development of m6A modifications in pathological pain provides a new angle of view. 84 Unfortunately, the current research on m6A and IBD is very limited, so the cognition of m6A is relatively limited. There is a need for relevant exploration to provide more possibilities for the pathogenesis, clinical diagnosis, and treatment application in IBD.…”