title: The DNMT1 intrinsically disordered domain regulates genomic methylation during development.
abstract: The DNMT1 cytosine methyltransferase enzyme contains a large ∼300-aa intrinsically disordered domain (IDD) that we previously showed regulated DNA methylation patterns in mouse ES cells. Here we generated seven mouse lines with different mutations in the IDD. Homozygous mutant mice of five lines developed normally, with normal levels of methylation on both imprinted and nonimprinted DNA sequences. The other two lines, however, had alterations in imprinted and/or nonimprinted (global) DNA methylation appearing during embryonic development. Embryos of one line expressing a DNMT1 variant containing a 6-aa rat orthologous sequence in the IDD maintained imprinted methylation, showed very reduced levels of global methylation and occasionally completed fetal development. These in vivo studies demonstrate that at least two DNMT1-dependent methylation processes can be distinguished during fetal development. One process maintains the bulk of genomic methylation on nonimprinted sequences. The other process maintains methylation on a much smaller class of sequences including but not limited to gametic differentially methylated domains (gDMDs) that transmit essential imprinted parent-specific methylation for embryonic development.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
authors.forename: Ben
authors.initials: B
authors.lastname: Shaffer
authors.affiliation: Departments of Pediatrics, Human Genetics and Pharmacology and Therapeutics, McGill University and the Research Institute of the McGill University Health Centre, Montreal Children's Hospital, Montreal, Quebec H3H 2Z3, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: McGraw
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
authors.forename: Siyu C
authors.initials: SC
authors.lastname: Xiao
authors.affiliation: Departments of Pediatrics, Human Genetics and Pharmacology and Therapeutics, McGill University and the Research Institute of the McGill University Health Centre, Montreal Children's Hospital, Montreal, Quebec H3H 2Z3, Canada.
authors.forename: Donovan
authors.initials: D
authors.lastname: Chan
authors.affiliation: Departments of Pediatrics, Human Genetics and Pharmacology and Therapeutics, McGill University and the Research Institute of the McGill University Health Centre, Montreal Children's Hospital, Montreal, Quebec H3H 2Z3, Canada.
authors.forename: Jacquetta
authors.initials: J
authors.lastname: Trasler
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 chaillet@pitt.edu.
authors.forename: J Richard
authors.initials: JR
authors.lastname: Chaillet
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism; D005091:Exons; D005260:Female; D018507:Gene Expression Regulation, Developmental; D056726:Genetic Association Studies; D016678:Genome; D055106:Genome-Wide Association Study; D064267:Intrinsically Disordered Proteins; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D054730:Protein Interaction Domains and Motifs; D016415:Sequence Alignment
chemical_list: D064267:Intrinsically Disordered Proteins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; C000619382:Dnmt1 protein, rat
keywords: DNA methylation; Dnmt1; genomic imprinting; intrinsically disordered protein; methyltransferase