title: Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq.
abstract: An extensive repertoire of modifications is known to underlie the versatile coding, structural and catalytic functions of RNA, but it remains largely uncharted territory. Although biochemical studies indicate that N(6)-methyladenosine (m(6)A) is the most prevalent internal modification in messenger RNA, an in-depth study of its distribution and functions has been impeded by a lack of robust analytical methods. Here we present the human and mouse m(6)A modification landscape in a transcriptome-wide manner, using a novel approach, m(6)A-seq, based on antibody-mediated capture and massively parallel sequencing. We identify over 12,000 m(6)A sites characterized by a typical consensus in the transcripts of more than 7,000 human genes. Sites preferentially appear in two distinct landmarks--around stop codons and within long internal exons--and are highly conserved between human and mouse. Although most sites are well preserved across normal and cancerous tissues and in response to various stimuli, a subset of stimulus-dependent, dynamically modulated sites is identified. Silencing the m(6)A methyltransferase significantly affects gene expression and alternative splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis. Our findings therefore suggest that RNA decoration by m(6)A has a fundamental role in regulation of gene expression.
authors.affiliation: Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Dominissini
authors.forename: Sharon
authors.initials: S
authors.lastname: Moshitch-Moshkovitz
authors.forename: Schraga
authors.initials: S
authors.lastname: Schwartz
authors.forename: Mali
authors.initials: M
authors.lastname: Salmon-Divon
authors.forename: Lior
authors.initials: L
authors.lastname: Ungar
authors.forename: Sivan
authors.initials: S
authors.lastname: Osenberg
authors.forename: Karen
authors.initials: K
authors.lastname: Cesarkas
authors.forename: Jasmine
authors.initials: J
authors.lastname: Jacob-Hirsch
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.forename: Martin
authors.initials: M
authors.lastname: Kupiec
authors.forename: Rotem
authors.initials: R
authors.lastname: Sorek
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000235:genetics*; D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D019143:Evolution, Molecular; D056945:Hep G2 Cells; D006801:Humans; D055442:Metabolome / Q000235:genetics; D008745:Methylation; D008780:Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D012335:RNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics
chemical_list: D012335:RNA, Ribosomal; D016601:RNA-Binding Proteins; D012313:RNA; D012343:RNA, Transfer; D008780:Methyltransferases; C468275:METTL3 protein, human; C022556:mRNA (2'-O-methyladenosine-N6-)-methyltransferase; D000241:Adenosine