The N6-methyladenosine (m6A)-forming enzyme METTL3 facilitates M1 macrophage polarization through the methylation of STAT1 mRNA
The N6-methyladenosine (m6A)-forming enzyme METTL3 facilitates M1 macrophage polarization through the methylation of STAT1 mRNA
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N-6-甲基腺苷 (m(6)A) 形成酶 METTL3 通过 STAT1 mRNA 的甲基化促进 M1 巨噬细胞极化
DOI：
10.1152/ajpcell.00212.2019
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发表时间：
2019-10-01
影响因子：
5.5
通讯作者：
Fu, Yi
中科院分区：
文献类型：
--
作者：
Liu, Yihan;Liu, Zhujiang;Fu, Yi
令人信服的证据表明，表观遗传调节编排动态巨噬细胞极化。N-6-甲基腺苷（m（6）A）甲基化是哺乳动物mRNA最丰富的表观遗传修饰。但其在巨噬细胞极化中的作用仍然完全未知。在这里，我们表明，m（6）A-催化酶甲基转移酶样3（胃L3）是特异性上调后，M1极化的小鼠巨噬细胞。此外，通过siRNA转染的胃L3敲低显著抑制M1，但增强M2，巨噬细胞极化。相反，其通过质粒转染的过表达极大地促进了Ml。但减弱了M2，巨噬细胞极化。进一步的甲基化RNA免疫沉淀和体外m（6）A甲基化分析表明，胃L3直接甲基化编码信号转导和转录激活因子1（STAT 1）的mRNA，STAT 1是控制M1巨噬细胞极化的主要转录因子，在其编码序列和3 '非翻译区。另外。胃L3介导的STAT 1 mRNA甲基化显著增加mRNA稳定性，随后上调STAT 1表达。总之，胃L3通过直接甲基化STAT 1 mRNA驱动M1巨噬细胞极化，可能作为抗炎靶点。
Compelling evidence indicates that epigenetic regulations orchestrate dynamic macrophage polarization. N-6-methyladenosine (m(6)A) methylation is the most abundant epigenetic modification of mammalian mRNA. but its role in macrophage polarization is still completely unknown. Here, we show that the m(6)A-catalytic enzyme methyltransferase like 3 (METTL3) is specifically upregulated following the Ml polarization of mouse macrophages. Furthermore, METTL3 knockdown through siRNA transfection markedly inhibited M1, but enhanced M2, macrophage polarization. Conversely, its overexpression via plasmid transfection greatly facilitated Ml. but attenuated M2, macrophage polarization. Further methylated RNA immunoprecipitation and in vitro m(6)A methylation assays suggested that METTL3 directly methylates mRNA encoding signal transducer and activator of transcription 1 (STAT1), a master transcription factor controlling M1 macrophage polarization, at its coding sequence and 3'-untranslated regions. In addition. METTL3-mediated STAT1 mRNA methylation significantly increased mRNA stability and subsequently upregulated STAT1 expression. In conclusion, METTL3 drives M1 macrophage polarization by directly methylating STAT1 mRNA, potentially serving as an anti-inflammatory target.