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

Abstract

N⁶-methyladenosine (m⁶A) 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 m⁶A modification to control mRNA maturation, translation and decay. m⁶A can also alter RNA structures to affect RNA–protein interactions in cells. Here, we show that m⁶A increases the accessibility of its surrounding RNA sequence to bind heterogeneous nuclear ribonucleoprotein G (HNRNPG). Furthermore, HNRNPG binds m⁶A-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 m⁶A methylation. We identified 13,191 m⁶A 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 m⁶A-dependent RNA structural alterations can promote direct binding of m⁶A-modified RNAs to low-complexity regions in RNA binding proteins.