title: Genome-wide bisulfite sequencing in zygotes identifies demethylation targets and maps the contribution of TET3 oxidation.
abstract: Fertilization triggers global erasure of paternal 5-methylcytosine as part of epigenetic reprogramming during the transition from gametic specialization to totipotency. This involves oxidation by TET3, but our understanding of its targets and the wider context of demethylation is limited to a small fraction of the genome. We employed an optimized bisulfite strategy to generate genome-wide methylation profiles of control and TET3-deficient zygotes, using SNPs to access paternal alleles. This revealed that in addition to pervasive removal from intergenic sequences and most retrotransposons, gene bodies constitute a major target of zygotic demethylation. Methylation loss is associated with zygotic genome activation and at gene bodies is also linked to increased transcriptional noise in early development. Our data map the primary contribution of oxidative demethylation to a subset of gene bodies and intergenic sequences and implicate redundant pathways at many loci. Unexpectedly, we demonstrate that TET3 activity also protects certain CpG islands against methylation buildup.
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK. Electronic address: julian.peat@babraham.ac.uk.
authors.forename: Julian R
authors.initials: JR
authors.lastname: Peat
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Wendy
authors.initials: W
authors.lastname: Dean
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Clark
authors.affiliation: Bioinformatics Group, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Felix
authors.initials: F
authors.lastname: Krueger
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Sébastien A
authors.initials: SA
authors.lastname: Smallwood
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ficz
authors.affiliation: European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Hinxton CB10 1SD, UK.
authors.forename: Jong Kyoung
authors.initials: JK
authors.lastname: Kim
authors.affiliation: European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Hinxton CB10 1SD, UK; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Marioni
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hore
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK. Electronic address: wolf.reik@babraham.ac.uk.
authors.forename: Wolf
authors.initials: W
authors.lastname: Reik
mesh_terms: D000818:Animals; D018899:CpG Islands; D019175:DNA Methylation; D021901:DNA, Intergenic / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D049308:Dioxygenases; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D018626:Retroelements; D015053:Zygote / Q000378:metabolism*
chemical_list: D021901:DNA, Intergenic; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D018626:Retroelements; D049308:Dioxygenases; C551915:Tet3 protein, mouse