The RNA Methyltransferase Complex of WTAP, METTL3, and METTL14 Regulates Mitotic Clonal Expansion in Adipogenesis.
The RNA Methyltransferase Complex of WTAP, METTL3, and METTL14 Regulates Mitotic Clonal Expansion in Adipogenesis.
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DOI：
10.1128/mcb.00116-18
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发表时间：
2018-08-15
影响因子：
5.3
通讯作者：
Ueki K
中科院分区：
文献类型：
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作者：
Kobayashi M;Ohsugi M;Sasako T;Awazawa M;Umehara T;Iwane A;Kobayashi N;Okazaki Y;Kubota N;Suzuki R;Waki H;Horiuchi K;Hamakubo T;Kodama T;Aoe S;Tobe K;Kadowaki T;Ueki K
脂肪细胞的分化受多种机制的调控，其中有丝分裂克隆扩增（MCE）是其中的关键步骤。虽然已知这一过程是由细胞周期调节剂调节的，但其确切机制尚不清楚。脂肪细胞的分化受多种机制的调控，其中有丝分裂克隆扩增（MCE）是其中的关键步骤。虽然已知这一过程是由细胞周期调节剂调节的，但其确切机制尚不清楚。n6 -甲基腺苷（m6A）转录后RNA修饰，其甲基化和去甲基化由各自的酶分子进行，最近被认为参与脂肪形成的调节。在这里，我们发现由Wilms肿瘤1相关蛋白（WTAP）、甲基转移酶样3 （METTL3）和METTL14组成的RNA n6 -腺苷甲基转移酶复合物通过促进脂肪形成过程中MCE的细胞周期转变积极控制脂肪形成。WTAP与METTL3和METTL14结合，在体外依赖RNA诱导脂肪形成，在细胞核内增加分布。这三种蛋白的敲低会导致细胞周期阻滞和脂肪形成受损，这与MCE期间抑制细胞周期蛋白A2上调有关，其敲低也会损害脂肪形成。与此一致的是，Wtap杂合基因敲除小鼠具有较小的脂肪细胞大小和数量，从而免受饮食诱导的肥胖的影响，从而改善了胰岛素敏感性。这些数据提供了一种通过WTAP-METTL3-METTL14复合物形成脂肪的机制，以及一种治疗肥胖和相关疾病的潜在策略。
Adipocyte differentiation is regulated by various mechanisms, of which mitotic clonal expansion (MCE) is a key step. Although this process is known to be regulated by cell cycle modulators, the precise mechanism remains unclear. Adipocyte differentiation is regulated by various mechanisms, of which mitotic clonal expansion (MCE) is a key step. Although this process is known to be regulated by cell cycle modulators, the precise mechanism remains unclear. N6-Methyladenosine (m6A) posttranscriptional RNA modification, whose methylation and demethylation are performed by respective enzyme molecules, has recently been suggested to be involved in the regulation of adipogenesis. Here, we show that an RNA N6-adenosine methyltransferase complex consisting of Wilms' tumor 1-associating protein (WTAP), methyltransferase like 3 (METTL3), and METTL14 positively controls adipogenesis by promoting cell cycle transition in MCE during adipogenesis. WTAP, coupled with METTL3 and METTL14, is increased and distributed in nucleus by the induction of adipogenesis dependently on RNA in vitro. Knockdown of each of these three proteins leads to cell cycle arrest and impaired adipogenesis associated with suppression of cyclin A2 upregulation during MCE, whose knockdown also impairs adipogenesis. Consistent with this, Wtap heterozygous knockout mice are protected from diet-induced obesity with smaller size and number of adipocytes, leading to improved insulin sensitivity. These data provide a mechanism for adipogenesis through the WTAP-METTL3-METTL14 complex and a potential strategy for treatment of obesity and associated disorders.