N6-甲基腺苷 (m6A) 是真核 mRNA 上最丰富的内部修饰。 m6A 在 mRNA 上的去甲基化是由脂肪量和肥胖相关蛋白 (FTO) 酶催化的，FTO 是非血红素 Fe(II) 和 2-酮戊二酸 (2-OG) 依赖性双加氧酶家族的成员。 FTO 活性和 m6A-mRNA 在包括癌症在内的多种疾病中失调，但调节 FTO 活性的内源信号分子尚未确定。在这里，我们表明一氧化氮（NO）通过直接与催化铁中心结合而成为 FTO 去甲基化酶活性的有效抑制剂，导致细胞中 mRNA 的全局 m6A 高甲基化，并导致 m6A 在 NO 调节的 mRNA 上的基因特异性富集成绩单。细胞培养和肿瘤异种移植模型均表明内源性 NO 合成可以调节 m6A-mRNA 水平和 m6A 相关基因的转录变化。这些结果在 NO 和 m6A-mRNA 调节之间建立了直接联系，并揭示了 NO 作为表观转录组内源性调节因子的新型信号传导机制。版权所有 © 2023 作者。由 Elsevier B.V. 出版。保留所有权利。

N6-methyladenosine (m6A) is the most abundant internal modification on eukaryotic mRNAs. Demethylation of m6A on mRNA is catalyzed by the enzyme fat mass and obesity-associated protein (FTO), a member of the nonheme Fe(II) and 2-oxoglutarate (2-OG)-dependent family of dioxygenases. FTO activity and m6A-mRNA are dysregulated in multiple diseases including cancers, yet endogenous signaling molecules that modulate FTO activity have not been identified. Here we show that nitric oxide (NO) is a potent inhibitor of FTO demethylase activity by directly binding to the catalytic iron center, which causes global m6A hypermethylation of mRNA in cells and results in gene-specific enrichment of m6A on mRNA of NO-regulated transcripts. Both cell culture and tumor xenograft models demonstrated that endogenous NO synthesis can regulate m6A-mRNA levels and transcriptional changes of m6A-associated genes. These results build a direct link between NO and m6A-mRNA regulation and reveal a novel signaling mechanism of NO as an endogenous regulator of the epitranscriptome.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.