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Regulation of Co-transcriptional Pre-mRNA Splicing by m6A through the Low-Complexity Protein hnRNPG.
Molecular Cell ( IF 14.5 ) Pub Date : 2019-08-21 , DOI: 10.1016/j.molcel.2019.07.005 Katherine I Zhou 1 , Hailing Shi 2 , Ruitu Lyu 2 , Adam C Wylder 3 , Żaneta Matuszek 4 , Jessica N Pan 4 , Chuan He 5 , Marc Parisien 6 , Tao Pan 7
Molecular Cell ( IF 14.5 ) Pub Date : 2019-08-21 , DOI: 10.1016/j.molcel.2019.07.005 Katherine I Zhou 1 , Hailing Shi 2 , Ruitu Lyu 2 , Adam C Wylder 3 , Żaneta Matuszek 4 , Jessica N Pan 4 , Chuan He 5 , Marc Parisien 6 , Tao Pan 7
Affiliation
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N6-methyladenosine (m6A) modification occurs co-transcriptionally and impacts pre-mRNA processing; however, the mechanism of co-transcriptional m6A-dependent alternative splicing regulation is still poorly understood. Heterogeneous nuclear ribonucleoprotein G (hnRNPG) is an m6A reader protein that binds RNA through RRM and Arg-Gly-Gly (RGG) motifs. Here, we show that hnRNPG directly binds to the phosphorylated carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII) using RGG motifs in its low-complexity region. Through interactions with the phosphorylated CTD and nascent RNA, hnRNPG associates co-transcriptionally with RNAPII and regulates alternative splicing transcriptome-wide. m6A near splice sites in nascent pre-mRNA modulates hnRNPG binding, which influences RNAPII occupancy patterns and promotes exon inclusion. Our results reveal an integrated mechanism of co-transcriptional m6A-mediated splicing regulation, in which an m6A reader protein uses RGG motifs to co-transcriptionally interact with both RNAPII and m6A-modified nascent pre-mRNA to modulate RNAPII occupancy and alternative splicing.
中文翻译：
m6A 通过低复杂性蛋白 hnRNPG 调节共转录前 mRNA 剪接。
N6-甲基腺苷 (m6A) 修饰以共转录方式发生并影响前 mRNA 加工；然而，对共转录 m6A 依赖性选择性剪接调节的机制仍知之甚少。异质核核糖核蛋白 G (hnRNPG) 是一种 m6A 读取蛋白，可通过 RRM 和 Arg-Gly-Gly (RGG) 基序结合 RNA。在这里，我们展示了 hnRNPG 在其低复杂性区域使用 RGG 基序直接与 RNA 聚合酶 II (RNAPII) 的磷酸化羧基末端结构域 (CTD) 结合。通过与磷酸化 CTD 和新生 RNA 的相互作用，hnRNPG 与 RNAPII 共转录相关联，并在转录组范围内调节选择性剪接。新生前 mRNA 中剪接位点附近的 m6A 调节 hnRNPG 结合，从而影响 RNAPII 占据模式并促进外显子包含。
更新日期：2019-08-22
中文翻译：
m6A 通过低复杂性蛋白 hnRNPG 调节共转录前 mRNA 剪接。
N6-甲基腺苷 (m6A) 修饰以共转录方式发生并影响前 mRNA 加工；然而，对共转录 m6A 依赖性选择性剪接调节的机制仍知之甚少。异质核核糖核蛋白 G (hnRNPG) 是一种 m6A 读取蛋白，可通过 RRM 和 Arg-Gly-Gly (RGG) 基序结合 RNA。在这里，我们展示了 hnRNPG 在其低复杂性区域使用 RGG 基序直接与 RNA 聚合酶 II (RNAPII) 的磷酸化羧基末端结构域 (CTD) 结合。通过与磷酸化 CTD 和新生 RNA 的相互作用，hnRNPG 与 RNAPII 共转录相关联，并在转录组范围内调节选择性剪接。新生前 mRNA 中剪接位点附近的 m6A 调节 hnRNPG 结合，从而影响 RNAPII 占据模式并促进外显子包含。
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