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

2013; Nature Portfolio; Volume: 17; Issue: 1 Linguagem: Inglês

10.1038/nn.3588

1546-1726

Jimmy Huynh, Paras Garg, Tin Htwe Thin, Seungyeul Yoo, Ranjan Dutta, Bruce D. Trapp, Vahram Haroutunian, Jun Zhu, Michael Donovan, Andrew J. Sharp, Patrizia Casaccia,

Histone Deacetylase Inhibitors Research

In this Resource, the authors generate a genome-wide methylation profile of DNA from the normal-appearing white matter of control and multiple sclerosis–affected brains and find subtle, but widely distributed, differences. In particular, they report that hypermethylated genes that regulate oligodendrocyte survival are also transcriptionally downregulated. 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.