Mutations in human DNA methyltransferase DNMT1 induce specific genome-wide epigenomic and transcriptomic changes in neurodevelopment

DNA methyltransferase type 1 (DNMT1) is a major enzyme involved in maintaining the methylation pattern after DNA replication. Mutations in DNMT1 have been associated with autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). We used fibroblasts, induced pluripotent stem cells (iPS...

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Veröffentlicht in:Human molecular genetics Jg. 32; H. 21; S. 3105
Hauptverfasser: Davis, Kasey N, Qu, Ping-Ping, Ma, Shining, Lin, Ling, Plastini, Melanie, Dahl, Niklas, Plazzi, Giuseppe, Pizza, Fabio, O'Hara, Ruth, Wong, Wing Hung, Hallmayer, Joachim, Mignot, Emmanuel, Zhang, Xianglong, Urban, Alexander E
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England 17.10.2023
Schlagworte:
Cerebellar Ataxia - genetics
Deafness - genetics
DNA
DNA (Cytosine-5-)-Methyltransferase 1 - genetics
DNA (Cytosine-5-)-Methyltransferases - genetics
DNA Methylation - genetics
Epigenomics
Humans
Mutation
Transcriptome - genetics
ISSN:1460-2083, 1460-2083
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Abstract DNA methyltransferase type 1 (DNMT1) is a major enzyme involved in maintaining the methylation pattern after DNA replication. Mutations in DNMT1 have been associated with autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). We used fibroblasts, induced pluripotent stem cells (iPSCs) and induced neurons (iNs) generated from patients with ADCA-DN and controls, to explore the epigenomic and transcriptomic effects of mutations in DNMT1. We show cell type-specific changes in gene expression and DNA methylation patterns. DNA methylation and gene expression changes were negatively correlated in iPSCs and iNs. In addition, we identified a group of genes associated with clinical phenotypes of ADCA-DN, including PDGFB and PRDM8 for cerebellar ataxia, psychosis and dementia and NR2F1 for deafness and optic atrophy. Furthermore, ZFP57, which is required to maintain gene imprinting through DNA methylation during early development, was hypomethylated in promoters and exhibited upregulated expression in patients with ADCA-DN in both iPSC and iNs. Our results provide insight into the functions of DNMT1 and the molecular changes associated with ADCA-DN, with potential implications for genes associated with related phenotypes.
AbstractList DNA methyltransferase type 1 (DNMT1) is a major enzyme involved in maintaining the methylation pattern after DNA replication. Mutations in DNMT1 have been associated with autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). We used fibroblasts, induced pluripotent stem cells (iPSCs) and induced neurons (iNs) generated from patients with ADCA-DN and controls, to explore the epigenomic and transcriptomic effects of mutations in DNMT1. We show cell type-specific changes in gene expression and DNA methylation patterns. DNA methylation and gene expression changes were negatively correlated in iPSCs and iNs. In addition, we identified a group of genes associated with clinical phenotypes of ADCA-DN, including PDGFB and PRDM8 for cerebellar ataxia, psychosis and dementia and NR2F1 for deafness and optic atrophy. Furthermore, ZFP57, which is required to maintain gene imprinting through DNA methylation during early development, was hypomethylated in promoters and exhibited upregulated expression in patients with ADCA-DN in both iPSC and iNs. Our results provide insight into the functions of DNMT1 and the molecular changes associated with ADCA-DN, with potential implications for genes associated with related phenotypes.
DNA methyltransferase type 1 (DNMT1) is a major enzyme involved in maintaining the methylation pattern after DNA replication. Mutations in DNMT1 have been associated with autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). We used fibroblasts, induced pluripotent stem cells (iPSCs) and induced neurons (iNs) generated from patients with ADCA-DN and controls, to explore the epigenomic and transcriptomic effects of mutations in DNMT1. We show cell type-specific changes in gene expression and DNA methylation patterns. DNA methylation and gene expression changes were negatively correlated in iPSCs and iNs. In addition, we identified a group of genes associated with clinical phenotypes of ADCA-DN, including PDGFB and PRDM8 for cerebellar ataxia, psychosis and dementia and NR2F1 for deafness and optic atrophy. Furthermore, ZFP57, which is required to maintain gene imprinting through DNA methylation during early development, was hypomethylated in promoters and exhibited upregulated expression in patients with ADCA-DN in both iPSC and iNs. Our results provide insight into the functions of DNMT1 and the molecular changes associated with ADCA-DN, with potential implications for genes associated with related phenotypes.DNA methyltransferase type 1 (DNMT1) is a major enzyme involved in maintaining the methylation pattern after DNA replication. Mutations in DNMT1 have been associated with autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). We used fibroblasts, induced pluripotent stem cells (iPSCs) and induced neurons (iNs) generated from patients with ADCA-DN and controls, to explore the epigenomic and transcriptomic effects of mutations in DNMT1. We show cell type-specific changes in gene expression and DNA methylation patterns. DNA methylation and gene expression changes were negatively correlated in iPSCs and iNs. In addition, we identified a group of genes associated with clinical phenotypes of ADCA-DN, including PDGFB and PRDM8 for cerebellar ataxia, psychosis and dementia and NR2F1 for deafness and optic atrophy. Furthermore, ZFP57, which is required to maintain gene imprinting through DNA methylation during early development, was hypomethylated in promoters and exhibited upregulated expression in patients with ADCA-DN in both iPSC and iNs. Our results provide insight into the functions of DNMT1 and the molecular changes associated with ADCA-DN, with potential implications for genes associated with related phenotypes.
Author Qu, Ping-Ping
Pizza, Fabio
Hallmayer, Joachim
Wong, Wing Hung
Plazzi, Giuseppe
Davis, Kasey N
O'Hara, Ruth
Zhang, Xianglong
Lin, Ling
Plastini, Melanie
Urban, Alexander E
Dahl, Niklas
Mignot, Emmanuel
Ma, Shining
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  organization: Department of Genetics, Stanford University School of Medicine, Palo Alto CA 94304, USA
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  surname: Qu
  fullname: Qu, Ping-Ping
  organization: Department of Genetics, Stanford University School of Medicine, Palo Alto CA 94304, USA
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  givenname: Shining
  surname: Ma
  fullname: Ma, Shining
  organization: Department of Statistics, Stanford University, Stanford, CA 94305, USA
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  organization: Center for Narcolepsy, Stanford University School of Medicine, Palo Alto, CA 94304, USA
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  surname: Urban
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  organization: Department of Genetics, Stanford University School of Medicine, Palo Alto CA 94304, USA
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CitedBy_id crossref_primary_10_1093_nar_gkaf130
crossref_primary_10_1007_s12311_025_01791_5
crossref_primary_10_1080_07391102_2024_2321510
crossref_primary_10_1266_ggs_25_00045
crossref_primary_10_3390_audiolres14010010
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Snippet DNA methyltransferase type 1 (DNMT1) is a major enzyme involved in maintaining the methylation pattern after DNA replication. Mutations in DNMT1 have been...
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SubjectTerms Cerebellar Ataxia - genetics
Deafness - genetics
DNA
DNA (Cytosine-5-)-Methyltransferase 1 - genetics
DNA (Cytosine-5-)-Methyltransferases - genetics
DNA Methylation - genetics
Epigenomics
Humans
Mutation
Transcriptome - genetics
Title Mutations in human DNA methyltransferase DNMT1 induce specific genome-wide epigenomic and transcriptomic changes in neurodevelopment
URI https://www.ncbi.nlm.nih.gov/pubmed/37584462
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