N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein

Nucleic Acids Res. 2017 Jun 2;45(10):6051-6063. doi: 10.1093/nar/gkx141.

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.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemistry
  • Alternative Splicing
  • Conserved Sequence
  • Gene Knockdown Techniques
  • HEK293 Cells
  • HeLa Cells
  • Heterogeneous-Nuclear Ribonucleoproteins / metabolism*
  • Humans
  • Methyltransferases / antagonists & inhibitors
  • Methyltransferases / genetics
  • Nucleic Acid Conformation*
  • Oligoribonucleotides / chemical synthesis
  • Oligoribonucleotides / chemistry
  • Oligoribonucleotides / metabolism
  • Phylogeny
  • Protein Binding
  • RNA / chemistry
  • RNA / metabolism*
  • RNA Interference
  • RNA, Long Noncoding / metabolism
  • RNA, Small Interfering / genetics
  • Sequence Analysis, RNA
  • Transcriptome

Substances

  • Heterogeneous-Nuclear Ribonucleoproteins
  • MALAT1 long non-coding RNA, human
  • Oligoribonucleotides
  • RNA, Long Noncoding
  • RNA, Small Interfering
  • heterogeneous nuclear ribonucleoprotein G, human
  • N6-methyladenosine (m6A)
  • RNA
  • METTL4 protein, human
  • Methyltransferases
  • METTL3 protein, human
  • Adenosine