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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Vydané v:Human molecular genetics Ročník 32; číslo 21; s. 3105
Hlavní autori: 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
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: England 17.10.2023
Predmet:
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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Shrnutí: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.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1460-2083
1460-2083
DOI:10.1093/hmg/ddad123