MicroRNA(miRNA)是一类约22nt大小的内源RNA，在基因表达中起着重要的调控作用，参与了多种生理和病理过程。miRNA生成是一个复杂的过程，初级miRNA(pri-miRNA)需要经过细胞核和细胞质内的一系列加工才能形成成熟的miRNA。
整个流程的第一步是microprocessor复合体加工pri-miRNA。microprocessor复合体由RNA结合蛋白DGCR8和内切酶Drosha组成，DGCR8负责识别pri-miRNA茎环结构，然后招募DROSHA切割双链RNA，生成前体miRNA(pre-miRNA)。虽然人们对pri-miRNA加工机制研究得比较透彻，但至今还不清楚DGCR8在众多转录本二级结构中识别并结合pri-miRNA的机制。
洛克菲勒大学的研究团队发现，m6A是促进miRNA生成的关键性转录后修饰。这项研究发表在三月十八日的Nature杂志上，文章的通讯作者是洛克菲勒大学副教授Sohail F. Tavazoie。Sohail F. Tavazoie博士致力于癌症研究，近半年来已经在Nature、Cell杂志上发表了多项重要成果。
RNA同时具有信息分子和调控分子的双重身份，它不仅将DNA的遗传信息传递给蛋白，也调节着许多生物学过程。而RNA的转录后修饰，为这种多样化的功能奠定了基础。RNA上有一百多种化学修饰，但绝大多数修饰的功能还不为人知。
N6-methyladenosine(m6A)是真核生物mRNA上最常见的一种转录后修饰，这种可逆的RNA甲基化修饰与人类疾病有关。研究者们已经陆续定位了哺乳动物转录组中的m6A，鉴定了这种动态修饰所需的“读”、“写”和“擦除”蛋白。不过，人们还不清楚m6A在哺乳动物发育过程中起到了什么具体作用。
Tavazoie等人在哺乳动物细胞中发现，METTL3(一种m6A甲基化酶)会使pri-miRNA甲基化，给它们打上标记以便DGCR8识别和加工。去除METTL3会减少DGCR8与pri-miRNA的结合，导致细胞内的成熟miRNA全面减少，而未加工的pri-miRNA在细胞中累积。
研究人员还通过体外实验证实了m6A(N6-methyladenosine)促进pri-miRNA加工的能力。进一步研究表明，METTL3能够全面推动miRNA的成熟，不存在细胞类型特异性。
原文链接：N6-methyladenosine marks primary microRNAs for processing
The first step in the biogenesis of microRNAs is the processing of primary microRNAs (pri-miRNAs) by the microprocessor complex, composed of the RNA-binding protein DGCR8 and the type III RNase DROSHA. This initial event requires recognition of the junction between the stem and the flanking single-stranded RNA of the pri-miRNA hairpin by DGCR8 followed by recruitment of DROSHA, which cleaves the RNA duplex to yield the pre-miRNA product. While the mechanisms underlying pri-miRNA processing have been determined, the mechanism by which DGCR8 recognizes and binds pri-miRNAs, as opposed to other secondary structures present in transcripts, is not understood. Here we find in mammalian cells that methyltransferase-like 3 (METTL3) methylates pri-miRNAs, marking them for recognition and processing by DGCR8. Consistent with this, METTL3 depletion reduced the binding of DGCR8 to pri-miRNAs and resulted in the global reduction of mature miRNAs and concomitant accumulation of unprocessed pri-miRNAs. In vitroprocessing reactions confirmed the sufficiency of the N6-methyladenosine (m6A) mark in promoting pri-miRNA processing. Finally, gain-of-function experiments revealed that METTL3 is sufficient to enhance miRNA maturation in a global and non-cell-type-specific manner. Our findings reveal that the m6A mark acts as a key post-transcriptional modification that promotes the initiation of miRNA biogenesis.
