Genomics

Dataset Information

296

Extensive changes in DNA methylation are associated with expression of mutant huntingtin [RRBS]


ABSTRACT: The earliest stages of Huntington’s disease are marked by changes in gene expression that are caused in an indirect and poorly understood manner by polyglutamine expansions in the huntingtin protein (HTT). To explore the hypothesis DNA methylation may be altered in cells expressing mutated HTT, we use reduced-representation bisulfite sequencing (RRBS) to map sites of DNA methylation in cells carrying either wild-type or mutant HTT. We find that a large fraction of the genes that change in expression in the presence of mutant huntingtin demonstrate significant changes in DNA methylation. Regions with low CpG content, which have previously been shown to undergo methylation changes in response to neuronal activity, are disproportionately affected. Based on the sequence of regions that change in methylation, we identify AP-1 and SOX2 as transcriptional regulators associated with DNA methylation changes, and we confirm these hypotheses using genome-wide chromatin immunoprecipitation (ChIP-Seq). Our findings suggest new mechanisms for the effects of polyglutamine-expanded HTT. These results also raise important questions about the potential effects of changes in DNA methylation on neurogenesis and at later stages, cognitive decline in Huntington’s patients. RRBS in STHdhQ7/Q7 and STHdhQ111/Q111 cells

ORGANISM(S): Mus musculus  

SUBMITTER: Christopher W Ng   Ernest Fraenkel  Christopher Ng 

PROVIDER: E-GEOD-43432 | ArrayExpress | 2013-01-24

SECONDARY ACCESSION(S): SRP017914GSE43432PRJNA186418

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications

Extensive changes in DNA methylation are associated with expression of mutant huntingtin.

Ng Christopher W CW   Yildirim Ferah F   Yap Yoon Sing YS   Dalin Simona S   Matthews Bryan J BJ   Velez Patricio J PJ   Labadorf Adam A   Housman David E DE   Fraenkel Ernest E  

Proceedings of the National Academy of Sciences of the United States of America 20130122 6


The earliest stages of Huntington disease are marked by changes in gene expression that are caused in an indirect and poorly understood manner by polyglutamine expansions in the huntingtin (HTT) protein. To explore the hypothesis that DNA methylation may be altered in cells expressing mutated HTT, we use reduced representation bisulfite sequencing (RRBS) to map sites of DNA methylation in cells carrying either wild-type or mutant HTT. We find that a large fraction of the genes that change in exp  ...[more]

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