title: In vivo control of CpG and non-CpG DNA methylation by DNA methyltransferases.
abstract: The enzymatic control of the setting and maintenance of symmetric and non-symmetric DNA methylation patterns in a particular genome context is not well understood. Here, we describe a comprehensive analysis of DNA methylation patterns generated by high resolution sequencing of hairpin-bisulfite amplicons of selected single copy genes and repetitive elements (LINE1, B1, IAP-LTR-retrotransposons, and major satellites). The analysis unambiguously identifies a substantial amount of regional incomplete methylation maintenance, i.e. hemimethylated CpG positions, with variant degrees among cell types. Moreover, non-CpG cytosine methylation is confined to ESCs and exclusively catalysed by Dnmt3a and Dnmt3b. This sequence position-, cell type-, and region-dependent non-CpG methylation is strongly linked to neighboring CpG methylation and requires the presence of Dnmt3L. The generation of a comprehensive data set of 146,000 CpG dyads was used to apply and develop parameter estimated hidden Markov models (HMM) to calculate the relative contribution of DNA methyltransferases (Dnmts) for de novo and maintenance DNA methylation. The comparative modelling included wild-type ESCs and mutant ESCs deficient for Dnmt1, Dnmt3a, Dnmt3b, or Dnmt3a/3b, respectively. The HMM analysis identifies a considerable de novo methylation activity for Dnmt1 at certain repetitive elements and single copy sequences. Dnmt3a and Dnmt3b contribute de novo function. However, both enzymes are also essential to maintain symmetrical CpG methylation at distinct repetitive and single copy sequences in ESCs.
authors: Department of Biological Sciences, Institute of Genetics/Epigenetics, University of Saarland, Saarbrücken, Germany.
authors: Julia
authors: J
authors: Arand
authors: David
authors: D
authors: Spieler
authors: Tommy
authors: T
authors: Karius
authors: Miguel R
authors: MR
authors: Branco
authors: Daniela
authors: D
authors: Meilinger
authors: Alexander
authors: A
authors: Meissner
authors: Thomas
authors: T
authors: Jenuwein
authors: Guoliang
authors: G
authors: Xu
authors: Heinrich
authors: H
authors: Leonhardt
authors: Verena
authors: V
authors: Wolf
authors: Jörn
authors: J
authors: Walter
mesh_terms: D000818:Animals; D002460:Cell Line; D018899:CpG Islands; D003596:Cytosine / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D053595:Embryonic Stem Cells / Q000166:cytology; D044127:Epigenesis, Genetic; D008745:Methylation; D051379:Mice; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D000097584:DNA Methyltransferase 3B
chemical_list: D003596:Cytosine; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D000097584:DNA Methyltransferase 3B; C000715535:Dnmt3a protein, mouse; C498796:Dnmt3l protein, mouse