title: Aberrant signature methylome by DNMT1 hot spot mutation in hereditary sensory and autonomic neuropathy 1E.
abstract: DNA methyltransferase 1 (DNMT1) is essential for DNA methylation, gene regulation and chromatin stability. We previously discovered DNMT1 mutations cause hereditary sensory and autonomic neuropathy type 1 with dementia and hearing loss (HSAN1E; OMIM 614116). HSAN1E is the first adult-onset neurodegenerative disorder caused by a defect in a methyltransferase gene. HSAN1E patients appear clinically normal until young adulthood, then begin developing the characteristic symptoms involving central and peripheral nervous systems. Some HSAN1E patients also develop narcolepsy and it has recently been suggested that HSAN1E is allelic to autosomal dominant cerebellar ataxia, deafness, with narcolepsy (ADCA-DN; OMIM 604121), which is also caused by mutations in DNMT1. A hotspot mutation Y495C within the targeting sequence domain of DNMT1 has been identified among HSAN1E patients. The mutant DNMT1 protein shows premature degradation and reduced DNA methyltransferase activity. Herein, we investigate genome-wide DNA methylation at single-base resolution through whole-genome bisulfite sequencing of germline DNA in 3 pairs of HSAN1E patients and their gender- and age-matched siblings. Over 1 billion 75-bp single-end reads were generated for each sample. In the 3 affected siblings, overall methylation loss was consistently found in all chromosomes with X and 18 being most affected. Paired sample analysis identified 564,218 differentially methylated CpG sites (DMCs; P<0.05), of which 300 134 were intergenic and 264 084 genic CpGs. Hypomethylation was predominant in both genic and intergenic regions, including promoters, exons, most CpG islands, L1, L2, Alu, and satellite repeats and simple repeat sequences. In some CpG islands, hypermethylated CpGs outnumbered hypomethylated CpGs. In 201 imprinted genes, there were more DMCs than in non-imprinted genes and most were hypomethylated. Differentially methylated region (DMR) analysis identified 5649 hypomethylated and 1872 hypermethylated regions. Importantly, pathway analysis revealed 1693 genes associated with the identified DMRs were highly associated in diverse neurological disorders and NAD+/NADH metabolism pathways is implicated in the pathogenesis. Our results provide novel insights into the epigenetic mechanism of neurodegeneration arising from a hotspot DNMT1 mutation and reveal pathways potentially important in a broad category of neurological and psychological disorders.
authors.affiliation: Division of Biomedical Statistics and Informatics; Mayo Clinic; Rochester, MN USA; Epigenomics Translational Program; Mayo Clinic Center for Individualized Medicine; Rochester, MN USA; Bioinformatics Program; Mayo Clinic Center for Individualized Medicine; Rochester, MN USA.
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Laboratory Medicine and Pathology; Mayo Clinic; Rochester, MN USA.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Epigenomics Translational Program; Mayo Clinic Center for Individualized Medicine; Rochester, MN USA; Department of Physiology and Biomedical Engineering; Mayo Clinic; Rochester, MN USA.
authors.forename: Tamas
authors.initials: T
authors.lastname: Ordog
authors.affiliation: Division of Biomedical Statistics and Informatics; Mayo Clinic; Rochester, MN USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Baheti
authors.affiliation: Division of Biomedical Statistics and Informatics; Mayo Clinic; Rochester, MN USA.
authors.forename: Jinfu
authors.initials: J
authors.lastname: Nie
authors.affiliation: Department of Neurology; Mayo Clinic; Rochester, MN USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Duan
authors.affiliation: Harima Sanatorium; Division of Neuropsychiatry; Hyogo, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Hojo
authors.affiliation: Division of Biomedical Statistics and Informatics; Mayo Clinic; Rochester, MN USA; Bioinformatics Program; Mayo Clinic Center for Individualized Medicine; Rochester, MN USA.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Kocher
authors.affiliation: Department of Neurology; Mayo Clinic; Rochester, MN USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dyck
authors.affiliation: Department of Laboratory Medicine and Pathology; Mayo Clinic; Rochester, MN USA; Department of Neurology; Mayo Clinic; Rochester, MN USA; Department of Medical Genetics; Mayo Clinic; Rochester, MN USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Klein
mesh_terms: D002675:Child, Preschool; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D050259:Genes, Mitochondrial; D018392:Genomic Imprinting; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009243:NAD / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017422:Sequence Analysis, DNA
chemical_list: D006657:Histones; D009243:NAD; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human
keywords: DNA methylation; HSAN1E; OMIM 604121; OMIM 614116; neurodegeneration; whole genome bisulfite sequencing