title: Transient DNMT1 suppression reveals hidden heritable marks in the genome.
abstract: Genome-wide demethylation and remethylation of DNA during early embryogenesis is essential for development. Imprinted germline differentially methylated domains (gDMDs) established by sex-specific methylation in either male or female germ cells, must escape these dynamic changes and sustain precise inheritance of both methylated and unmethylated parental alleles. To identify other, gDMD-like sequences with the same epigenetic inheritance properties, we used a modified embryonic stem (ES) cell line that emulates the early embryonic demethylation and remethylation waves. Transient DNMT1 suppression revealed gDMD-like sequences requiring continuous DNMT1 activity to sustain a highly methylated state. Remethylation of these sequences was also compromised in vivo in a mouse model of transient DNMT1 loss in the preimplantation embryo. These novel regions, possessing heritable epigenetic features similar to imprinted-gDMDs are required for normal physiological and developmental processes and when disrupted are associated with disorders such as cancer and autism spectrum disorders. This study presents new perspectives on DNA methylation heritability during early embryo development that extend beyond conventional imprinted-gDMDs.
authors.affiliation: Departments of Pediatrics, Human Genetics and Pharmacology & Therapeutics, McGill University and the Research Institute of the McGill University Health Centre at the Montreal Children's Hospital, Montreal, QC H3Z 2Z3, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: McGraw
authors.affiliation: Departments of Pediatrics, Human Genetics and Pharmacology & Therapeutics, McGill University and the Research Institute of the McGill University Health Centre at the Montreal Children's Hospital, Montreal, QC H3Z 2Z3, Canada.
authors.forename: Jacques X
authors.initials: JX
authors.lastname: Zhang
authors.affiliation: Departments of Pediatrics, Human Genetics and Pharmacology & Therapeutics, McGill University and the Research Institute of the McGill University Health Centre at the Montreal Children's Hospital, Montreal, QC H3Z 2Z3, Canada.
authors.forename: Mena
authors.initials: M
authors.lastname: Farag
authors.affiliation: Departments of Pediatrics, Human Genetics and Pharmacology & Therapeutics, McGill University and the Research Institute of the McGill University Health Centre at the Montreal Children's Hospital, Montreal, QC H3Z 2Z3, Canada.
authors.forename: Donovan
authors.initials: D
authors.lastname: Chan
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 1A4, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Caron
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg 69120, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Konermann
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg 69120, Germany.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Oakes
authors.affiliation: Department of Biological Sciences, Birla Institute of Technology and Science Pilani, Hyderabad 500 078, India.
authors.forename: K Naga
authors.initials: KN
authors.lastname: Mohan
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg 69120, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 1A4, Canada.
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 1A4, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bourque
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15213-3005, USA.
authors.forename: J Richard
authors.initials: JR
authors.lastname: Chaillet
authors.affiliation: Departments of Pediatrics, Human Genetics and Pharmacology & Therapeutics, McGill University and the Research Institute of the McGill University Health Centre at the Montreal Children's Hospital, Montreal, QC H3Z 2Z3, Canada jacquetta.trasler@mcgill.ca.
authors.forename: Jacquetta M
authors.initials: JM
authors.lastname: Trasler
mesh_terms: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D015894:Genome, Human; D006801:Humans
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse