title: Identification of epigenetically altered genes in sporadic amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a terminal disease involving the progressive degeneration of motor neurons within the motor cortex, brainstem and spinal cord. Most cases are sporadic (sALS) with unknown causes suggesting that the etiology of sALS may not be limited to the genotype of patients, but may be influenced by exposure to environmental factors. Alterations in epigenetic modifications are likely to play a role in disease onset and progression in ALS, as aberrant epigenetic patterns may be acquired throughout life. The aim of this study was to identify epigenetic marks associated with sALS. We hypothesize that epigenetic modifications may alter the expression of pathogenesis-related genes leading to the onset and progression of sALS. Using ELISA assays, we observed alterations in global methylation (5 mC) and hydroxymethylation (5 HmC) in postmortem sALS spinal cord but not in whole blood. Loci-specific differentially methylated and expressed genes in sALS spinal cord were identified by genome-wide 5mC and expression profiling using high-throughput microarrays. Concordant direction, hyper- or hypo-5mC with parallel changes in gene expression (under- or over-expression), was observed in 112 genes highly associated with biological functions related to immune and inflammation response. Furthermore, literature-based analysis identified potential associations among the epigenes. Integration of methylomics and transcriptomics data successfully revealed methylation changes in sALS spinal cord. This study represents an initial identification of epigenetic regulatory mechanisms in sALS which may improve our understanding of sALS pathogenesis for the identification of biomarkers and new therapeutic targets.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Claudia
authors.initials: C
authors.lastname: Figueroa-Romero
authors.forename: Junguk
authors.initials: J
authors.lastname: Hur
authors.forename: Diane E
authors.initials: DE
authors.lastname: Bender
authors.forename: Colin E
authors.initials: CE
authors.lastname: Delaney
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cataldo
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Smith
authors.forename: Raymond
authors.initials: R
authors.lastname: Yung
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Ruden
authors.forename: Brian C
authors.initials: BC
authors.lastname: Callaghan
authors.forename: Eva L
authors.initials: EL
authors.lastname: Feldman
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D003562:Cytidine / Q000031:analogs & derivatives / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D013116:Spinal Cord / Q000378:metabolism; D059467:Transcriptome
chemical_list: D003562:Cytidine; C016568:5-methylcytidine