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Nat Neurosci. 2014 Jan;17(1):121-30. doi: 10.1038/nn.3588. Epub 2013 Nov 24.

Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains.

Author information

1
1] Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
2
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
3
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
4
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
5
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
6
1] Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3] Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Abstract

Using the Illumina 450K array and a stringent statistical analysis with age and gender correction, we report genome-wide differences in DNA methylation between pathology-free regions derived from human multiple sclerosis-affected and control brains. Differences were subtle, but widespread and reproducible in an independent validation cohort. The transcriptional consequences of differential DNA methylation were further defined by genome-wide RNA-sequencing analysis and validated in two independent cohorts. Genes regulating oligodendrocyte survival, such as BCL2L2 and NDRG1, were hypermethylated and expressed at lower levels in multiple sclerosis-affected brains than in controls, while genes related to proteolytic processing (for example, LGMN, CTSZ) were hypomethylated and expressed at higher levels. These results were not due to differences in cellular composition between multiple sclerosis and controls. Thus, epigenomic changes in genes affecting oligodendrocyte susceptibility to damage are detected in pathology-free areas of multiple sclerosis-affected brains.

PMID:
24270187
PMCID:
PMC3934491
DOI:
10.1038/nn.3588
[Indexed for MEDLINE]
Free PMC Article

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