N-methyladenosine (mA) modification occurs co-transcriptionally and impacts pre-mRNA processing; however, the mechanism of co-transcriptional mA-dependent alternative splicing regulation is still poorly understood. Heterogeneous nuclear ribonucleoprotein G (hnRNPG) is an mA 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. mA 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 mA-mediated splicing regulation, in which an mA reader protein uses RGG motifs to co-transcriptionally interact with both RNAPII and mA-modified nascent pre-mRNA to modulate RNAPII occupancy and alternative splicing.
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| http://dx.doi.org/10.1016/j.molcel.2019.07.005 | DOI Listing |
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