N (6)-methyladenosine alters RNA structure to regulate binding of a low-complexity protein

N (6)-methyladenosine (m(6)A) is the most abundant internal modification in eukaryotic messenger RNA (mRNA), and affects almost every stage of the mRNA life cycle. The YTH-domain proteins can specifically recognize m(6)A modification to control mRNA maturation, translation and decay. m(6)A can also alter RNA structures to affect RNA–protein interactions in cells. Here, we show that m(6)A increases the accessibility of its surrounding RNA sequence to bind heterogeneous nuclear ribonucleoprotein G (HNRNPG). Furthermore, HNRNPG binds m(6)A-methylated RNAs through its C-terminal low-complexity region, which self-assembles into large particles in vitro. The Arg-Gly-Gly repeats within the low-complexity region are required for binding to the RNA motif exposed by m(6)A methylation. We identified 13,191 m(6)A sites in the transcriptome that regulate RNA–HNRNPG interaction and thereby alter the expression and alternative splicing pattern of target mRNAs. Low-complexity regions are pervasive among mRNA binding proteins. Our results show that m(6)A-dependent RNA structural alterations can promote direct binding of m(6)A-modified RNAs to low-complexity regions in RNA binding proteins.