[PDF][PDF] Regulation of co-transcriptional pre-mRNA splicing by m6A through the low-complexity protein hnRNPG

KI Zhou, H Shi, R Lyu, AC Wylder, Ż Matuszek, JN Pan… - Molecular cell, 2019 - cell.com
KI Zhou, H Shi, R Lyu, AC Wylder, Ż Matuszek, JN Pan, C He, M Parisien, T Pan
Molecular cell, 2019cell.com
Summary N 6-methyladenosine (m 6 A) modification occurs co-transcriptionally and impacts
pre-mRNA processing; however, the mechanism of co-transcriptional m 6 A-dependent
alternative splicing regulation is still poorly understood. Heterogeneous nuclear
ribonucleoprotein G (hnRNPG) is an m 6 A 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 …
Summary
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.
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