Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5' sites.
Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5' sites.
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DOI：
10.1016/j.celrep.2014.05.048
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发表时间：
2014-07-10
期刊：
影响因子：
8.8
通讯作者：
Regev A
中科院分区：
文献类型：
--
作者：
Schwartz S;Mumbach MR;Jovanovic M;Wang T;Maciag K;Bushkin GG;Mertins P;Ter-Ovanesyan D;Habib N;Cacchiarelli D;Sanjana NE;Freinkman E;Pacold ME;Satija R;Mikkelsen TS;Hacohen N;Zhang F;Carr SA;Lander ES;Regev A
N6-甲基腺苷（m6 A）是一种常见的mRNA修饰，在微调RNA生命周期中具有潜在的作用。在这里，我们确定了与甲基转移酶复合物的一个组成部分--胃L3相互作用的蛋白质的密集网络，并表明其中三个蛋白质WTAP、胃L14和KIAA 1429是甲基化所必需的。WTAP耗竭后监测m6 A水平允许定义准确和接近单核苷酸分辨率的甲基化图谱，并将其分类为WTAP依赖性和独立位点。WTAP依赖性位点位于转录本的内部位置，在我们调查的各种系统中是拓扑静态的，并且与mRNA稳定性呈负相关，这与建立“基础”降解率的作用一致。WTAP独立位点在第一个转录碱基处形成，作为帽结构的一部分，并存在于数千个位点上，形成了以前未被认识到的转录组复杂性层。我们的数据揭示了这种epitranscriptomic修饰的蛋白质组学和转录基础。
N6-methyladenosine (m6A) is a common modification of mRNA, with potential roles in fine-tuning the RNA life-cycle. Here, we identify a dense network of proteins interacting with METTL3, a component of the methyltransferase complex, and show that three of them, WTAP, METTL14 and KIAA1429, are required for methylation. Monitoring m6A levels upon WTAP depletion allowed the definition of accurate and near single-nucleotide resolution methylation maps, and their classification into WTAP-dependent and independent sites. WTAP-dependent sites are located at internal positions in transcripts, are topologically static across a variety of systems we surveyed, and are inversely correlated with mRNA stability, consistent with a role in establishing ‘basal’ degradation rates. WTAP-independent sites form at the first transcribed base as part of the cap structure, and are present at thousands of sites, forming a previously unappreciated layer of transcriptome complexity. Our data sheds new light on proteomic and transcriptional underpinnings of this epitranscriptomic modification.
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