title: Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains.
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.
authors.affiliation: 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.
authors.forename: Jimmy L
authors.initials: JL
authors.lastname: Huynh
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Paras
authors.initials: P
authors.lastname: Garg
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Tin Htwe
authors.initials: TH
authors.lastname: Thin
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Seungyeul
authors.initials: S
authors.lastname: Yoo
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Ranjan
authors.initials: R
authors.lastname: Dutta
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Trapp
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Donovan
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sharp
authors.affiliation: 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.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Casaccia
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D063990:Gene Ontology; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D009103:Multiple Sclerosis / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000473:pathology; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D006684:HLA-DR Antigens; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C491073:BCL2L2 protein, human; C405708:OLIG2 protein, human