N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions.
N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions.
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n（6） - 甲基腺苷依赖性RNA结构开关调节RNA蛋白质相互作用。
DOI：
10.1038/nature14234
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发表时间：
2015-02-26
期刊：
影响因子：
64.8
通讯作者：
Pan, Tao
中科院分区：
文献类型：
--
作者：
Liu, Nian;Dai, Qing;Zheng, Guanqun;He, Chuan;Parisien, Marc;Pan, Tao
RNA结合蛋白通过结合单链RNA结合基序（RBM）控制细胞生物学的许多方面。然而，RBM可以被埋在它们的局部RNA结构中，从而抑制RNA-蛋白质相互作用。N6-甲基腺苷（m6 A）是真核生物信使RNA中最丰富和动态的内部修饰，可被YTHDF 2蛋白选择性识别，影响胞质mRNA的稳定性，但m6 A如何发挥广泛的生理意义尚需进一步探索。在这里，我们表明，m6 A控制的RNA结构依赖的RBM的可访问性，影响RNA-蛋白质相互作用的生物调节，我们把这种机制“m6 A开关”。我们发现m6 A改变了mRNA和长链非编码RNA（lncRNA）的局部结构，以促进异质核核糖核蛋白C（hnRNP C）的结合，hnRNP C是一种丰富的核RNA结合蛋白，负责前mRNA加工。结合PAR-CLIP和m6 A/MeRIP方法使我们能够在hnRNP C结合位点中鉴定39，060个m6 A-开关;并且在2，798个高置信度m6 A-开关处，全局m6 A减少降低了hnRNP C结合。我们确定这些m6 A开关调节的hnRNP C结合活性影响靶mRNA的丰度以及选择性剪接，证明了m6 A开关对基因表达和RNA成熟的调节作用。我们的研究结果说明了RNA结合蛋白如何通过m6 A依赖的RNA结构重塑获得对其RBM的调控，并为研究RNA修饰编码的细胞生物学提供了新的方向。
RNA-binding proteins control many aspects of cellular biology through binding single-stranded RNA binding motifs (RBM). However, RBMs can be buried within their local RNA structures, thus inhibiting RNA-protein interactions. N6-methyladenosine (m6A), the most abundant and dynamic internal modification in eukaryotic messenger RNA, can be selectively recognized by the YTHDF2 protein to affect the stability of cytoplasmic mRNAs, but how m6A achieves wide-ranging physiological significance needs further exploration. Here we show that m6A controls the RNA-structure-dependent accessibility of RBMs to affect RNA-protein interactions for biological regulation; we term this mechanism “m6A-switch”. We found that m6A alters the local structure in mRNA and long non-coding RNA (lncRNA) to facilitate binding of heterogeneous nuclear ribonucleoprotein C (hnRNP C), an abundant nuclear RNA-binding protein responsible for pre-mRNA processing. Combining PAR-CLIP and m6A/MeRIP approaches enabled us to identify 39,060 m6A-switches among hnRNP C binding sites; and global m6A reduction decreased hnRNP C binding at 2,798 high confidence m6A-switches. We determined that these m6A-switch-regulated hnRNP C binding activities affect the abundance as well as alternative splicing of target mRNAs, demonstrating the regulatory role of m6A-switches on gene expression and RNA maturation. Our results illustrate how RNA-binding proteins gain regulated access to their RBMs through m6A-dependent RNA structural remodeling, and provide a new direction for investigating RNA-modification-coded cellular biology.
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影响因子：
15
作者：
Cienikova, Zuzana;Damberger, Fred F.;Maris, Christophe
通讯作者：
Maris, Christophe
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Schwartz S;Agarwala SD;Mumbach MR;Jovanovic M;Mertins P;Shishkin A;Tabach Y;Mikkelsen TS;Satija R;Ruvkun G;Carr SA;Lander ES;Fink GR;Regev A
通讯作者：
Regev A
影响因子：
64.5
作者：
Hafner M;Landthaler M;Burger L;Khorshid M;Hausser J;Berninger P;Rothballer A;Ascano M Jr;Jungkamp AC;Munschauer M;Ulrich A;Wardle GS;Dewell S;Zavolan M;Tuschl T
通讯作者：
Tuschl T
影响因子：
23.9
作者：
Batista, Pedro J.;Molinie, Benoit;Wang, Jinkai;Qu, Kun;Zhang, Jiajing;Li, Lingjie;Bouley, Donna M.;Lujan, Ernesto;Haddad, Bahareh;Daneshvar, Kaveh;Carter, Ava C.;Flynn, Ryan A.;Zhou, Chan;Lim, Kok-Seong;Dedon, Peter;Wernig, Marius;Mullen, Alan C.;Xing, Yi;Giallourakis, Cosmas C.;Chang, Howard Y.
通讯作者：
Chang, Howard Y.