N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein.
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.
Department of Chemistry, University of Chicago, Chicago, IL 60637, USA.
Nian
N
Liu
Medical Scientist Training Program, University of Chicago, Chicago, IL 60637, USA.
Katherine I
KI
Zhou
The Alan Edwards Centre for Research on Pain, Department of Dentistry, McGill University, Montréal, Québec H3A 0G1, Canada.
Marc
M
Parisien
Department of Chemistry, University of Chicago, Chicago, IL 60637, USA.
Qing
Q
Dai
The Alan Edwards Centre for Research on Pain, Department of Dentistry, McGill University, Montréal, Québec H3A 0G1, Canada.
Luda
L
Diatchenko
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.|Institute of Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
Tao
T
Pan
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry; D017398:Alternative Splicing; D017124:Conserved Sequence; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism*; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics; D009690:Nucleic Acid Conformation; D009843:Oligoribonucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D010802:Phylogeny; D011485:Protein Binding; D012313:RNA / Q000737:chemistry / Q000378:metabolism*; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017423:Sequence Analysis, RNA; D059467:Transcriptome
D034441:Heterogeneous-Nuclear Ribonucleoproteins; C557041:MALAT1 long non-coding RNA, human; D009843:Oligoribonucleotides; C510272:RBMX protein, human; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; D012313:RNA; C010223:N-methyladenosine; C586526:METTL4 protein, human; D008780:Methyltransferases; C468275:METTL3 protein, human; D000241:Adenosine