Monozygotic twins and triplets discordant for amyotrophic lateral sclerosis display differential methylation and gene expression.

Autor: Tarr IS; Centre for Motor Neuron Disease Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia., McCann EP; Centre for Motor Neuron Disease Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia., Benyamin B; Australian Centre for Precision Health, University of South Australia Cancer Research Institute, School of Health Sciences, University of South Australia, Adelaide, Australia.; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia., Peters TJ; Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia., Twine NA; Health and Biosecurity Business Unit, Commonwealth Scientific and Industrial Research Organisation, Sydney, New South Wales, Australia., Zhang KY; Centre for Motor Neuron Disease Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia., Zhao Q; Queensland Brain Institute, University of Queensland, Queensland, Australia., Zhang ZH; Queensland Brain Institute, University of Queensland, Queensland, Australia., Rowe DB; Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia., Nicholson GA; ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia.; Molecular Medicine Laboratory, Concord Hospital, Sydney, New South Wales, Australia., Bauer D; Health and Biosecurity Business Unit, Commonwealth Scientific and Industrial Research Organisation, Sydney, New South Wales, Australia., Clark SJ; Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.; St Vincent's Clinical School, UNSW Sydney, New South Wales, Australia., Blair IP; Centre for Motor Neuron Disease Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia., Williams KL; Centre for Motor Neuron Disease Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia. kelly.williams@mq.edu.au.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2019 Jun 04; Vol. 9 (1), pp. 8254. Date of Electronic Publication: 2019 Jun 04.
DOI: 10.1038/s41598-019-44765-4
Abstrakt: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons. ALS exhibits high phenotypic variability including age and site of onset, and disease duration. To uncover epigenetic and transcriptomic factors that may modify an ALS phenotype, we used a cohort of Australian monozygotic twins (n = 3 pairs) and triplets (n = 1 set) that are discordant for ALS and represent sporadic ALS and the two most common types of familial ALS, linked to C9orf72 and SOD1. Illumina Infinium HumanMethylation450K BeadChip, EpiTYPER and RNA-Seq analyses in these ALS-discordant twins/triplets and control twins (n = 2 pairs), implicated genes with consistent longitudinal differential DNA methylation and/or gene expression. Two identified genes, RAD9B and C8orf46, showed significant differential methylation in an extended cohort of >1000 ALS cases and controls. Combined longitudinal methylation-transcription analysis within a single twin set implicated CCNF, DPP6, RAMP3, and CCS, which have been previously associated with ALS. Longitudinal transcriptome data showed an 8-fold enrichment of immune function genes and under-representation of transcription and protein modification genes in ALS. Examination of these changes in a large Australian sporadic ALS cohort suggest a broader role in ALS. Furthermore, we observe that increased methylation age is a signature of ALS in older patients.
Databáze: MEDLINE
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