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Nat Methods. 2016 Aug;13(8):692-8. doi: 10.1038/nmeth.3898. Epub 2016 Jul 4.

m(6)A-LAIC-seq reveals the census and complexity of the m(6)A epitranscriptome.

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Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
Center for Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.


N(6)-Methyladenosine (m(6)A) is a widespread, reversible chemical modification of RNA molecules, implicated in many aspects of RNA metabolism. Little quantitative information exists as to either how many transcript copies of particular genes are m(6)A modified ('m(6)A levels') or the relationship of m(6)A modification(s) to alternative RNA isoforms. To deconvolute the m(6)A epitranscriptome, we developed m(6)A-level and isoform-characterization sequencing (m(6)A-LAIC-seq). We found that cells exhibit a broad range of nonstoichiometric m(6)A levels with cell-type specificity. At the level of isoform characterization, we discovered widespread differences in the use of tandem alternative polyadenylation (APA) sites by methylated and nonmethylated transcript isoforms of individual genes. Strikingly, there is a strong bias for methylated transcripts to be coupled with proximal APA sites, resulting in shortened 3' untranslated regions, while nonmethylated transcript isoforms tend to use distal APA sites. m(6)A-LAIC-seq yields a new perspective on transcriptome complexity and links APA usage to m(6)A modifications.

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