title: Intragenic DNA methylation prevents spurious transcription initiation.
abstract: In mammals, DNA methylation occurs mainly at CpG dinucleotides. Methylation of the promoter suppresses gene expression, but the functional role of gene-body DNA methylation in highly expressed genes has yet to be clarified. Here we show that, in mouse embryonic stem cells, Dnmt3b-dependent intragenic DNA methylation protects the gene body from spurious RNA polymerase II entry and cryptic transcription initiation. Using different genome-wide approaches, we demonstrate that this Dnmt3b function is dependent on its enzymatic activity and recruitment to the gene body by H3K36me3. Furthermore, the spurious transcripts can either be degraded by the RNA exosome complex or capped, polyadenylated, and delivered to the ribosome to produce aberrant proteins. Elongating RNA polymerase II therefore triggers an epigenetic crosstalk mechanism that involves SetD2, H3K36me3, Dnmt3b and DNA methylation to ensure the fidelity of gene transcription initiation, with implications for intragenic hypomethylation in cancer.
authors.affiliation: Human Genetics Foundation (HuGeF), via Nizza 52, 10126 Torino, Italy.|Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Francesco
authors.initials: F
authors.lastname: Neri
authors.affiliation: Dipartimento di Scienze della Vita e Biologia dei Sistemi, Università di Torino, via Accademia Albertina 13, 10123 Torino, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Rapelli
authors.affiliation: Human Genetics Foundation (HuGeF), via Nizza 52, 10126 Torino, Italy.|Dipartimento di Scienze della Vita e Biologia dei Sistemi, Università di Torino, via Accademia Albertina 13, 10123 Torino, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Krepelova
authors.affiliation: Human Genetics Foundation (HuGeF), via Nizza 52, 10126 Torino, Italy.
authors.forename: Danny
authors.initials: D
authors.lastname: Incarnato
authors.affiliation: Human Genetics Foundation (HuGeF), via Nizza 52, 10126 Torino, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Parlato
authors.affiliation: Human Genetics Foundation (HuGeF), via Nizza 52, 10126 Torino, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Basile
authors.affiliation: Human Genetics Foundation (HuGeF), via Nizza 52, 10126 Torino, Italy.|Dipartimento di Scienze della Vita e Biologia dei Sistemi, Università di Torino, via Accademia Albertina 13, 10123 Torino, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Maldotti
authors.affiliation: Human Genetics Foundation (HuGeF), via Nizza 52, 10126 Torino, Italy.|Dipartimento di Scienze della Vita e Biologia dei Sistemi, Università di Torino, via Accademia Albertina 13, 10123 Torino, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Anselmi
authors.affiliation: Human Genetics Foundation (HuGeF), via Nizza 52, 10126 Torino, Italy.|Dipartimento di Scienze della Vita e Biologia dei Sistemi, Università di Torino, via Accademia Albertina 13, 10123 Torino, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oliviero
mesh_terms: D000818:Animals; D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005796:Genes / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D026723:Polyadenylation; D012315:RNA Caps / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D024363:Transcription Initiation Site; D061785:Transcription Initiation, Genetic; D000097584:DNA Methyltransferase 3B
chemical_list: D004247:DNA; D004248:DNA (Cytosine-5-)-Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D008239:Lysine; D012315:RNA Caps; D012319:RNA Polymerase II; D012333:RNA, Messenger; D000097584:DNA Methyltransferase 3B; C587921:SETD2 protein, mouse