Genome-Wide Maps of m6A circRNAs Identify Widespread and Cell-Type-Specific Methylation Patterns that Are Distinct from mRNAs

Cell Rep. 2017 Aug 29;20(9):2262-2276. doi: 10.1016/j.celrep.2017.08.027.

Abstract

N6-methyladenosine (m6A) is the most abundant internal modification of mRNAs and is implicated in all aspects of post-transcriptional RNA metabolism. However, little is known about m6A modifications to circular (circ) RNAs. We developed a computational pipeline (AutoCirc) that, together with depletion of ribosomal RNA and m6A immunoprecipitation, defined thousands of m6A circRNAs with cell-type-specific expression. The presence of m6A circRNAs is corroborated by interaction between circRNAs and YTHDF1/YTHDF2, proteins that read m6A sites in mRNAs, and by reduced m6A levels upon depletion of METTL3, the m6A writer. Despite sharing m6A readers and writers, m6A circRNAs are frequently derived from exons that are not methylated in mRNAs, whereas mRNAs that are methylated on the same exons that compose m6A circRNAs exhibit less stability in a process regulated by YTHDF2. These results expand our understanding of the breadth of m6A modifications and uncover regulation of circRNAs through m6A modification.

Keywords: METTL3; YTHDF2; circular RNAs; embryonic stem cells; m6A modification; methyladenosine; noncoding RNAs.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Base Sequence
  • Computational Biology
  • DNA Transposable Elements / genetics
  • Exons / genetics
  • Exoribonucleases / metabolism
  • Gene Expression Regulation
  • Genome, Human*
  • Half-Life
  • HeLa Cells
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Methylation
  • Methyltransferases / metabolism
  • RNA / genetics
  • RNA / metabolism*
  • RNA Stability
  • RNA, Circular
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / metabolism

Substances

  • DNA Transposable Elements
  • RNA, Circular
  • RNA, Messenger
  • RNA-Binding Proteins
  • YTHDF1 protein, human
  • YTHDF2 protein, human
  • RNA
  • N-methyladenosine
  • METTL14 protein, human
  • Methyltransferases
  • METTL3 protein, human
  • Exoribonucleases
  • ribonuclease R
  • Adenosine