Repetitive element hypermethylation in multiple sclerosis patients

Abstract

BackgroundMultiple sclerosis (MS) is a complex disorder of the central nervous system whose cause is currently unknown. Evidence is increasing that DNA methylation alterations could be involved in inflammatory and neurodegenerative diseases and could contribute to MS pathogenesis. Repetitive elements Alu, LINE-1 and SAT-α, are widely known as estimators of global DNA methylation. We investigated Alu, LINE-1 and SAT-α methylation levels to evaluate their difference in a case–control setup and their role as a marker of disability.ResultsWe obtained blood samples from 51 MS patients and 137 healthy volunteers matched by gender, age and smoking. Methylation was assessed using bisulfite-PCR-pyrosequencing. For all participants, medical history, physical and neurological examinations and screening laboratory tests were collected. All repetitive elements were hypermethylated in MS patients compared to healthy controls. A lower Expanded Disability Status Scale (EDSS) score was associated with a lower levels of LINE-1 methylation for ‘EDSS = 1.0’ and ‘1.5 ≤ EDSS ≤ 2.5’ compared to an EDSS higher than 3, while Alu was associated with a higher level of methylation in these groups: ‘EDSS = 1.0’ and ‘1.5 ≤ EDSS ≤ 2.5’.ConclusionsMS patients exhibit an hypermethylation in repetitive elements compared to healthy controls. Alu and LINE-1 were associated with degree of EDSS score. Forthcoming studies focusing on epigenetics and the multifactorial pathogenetic mechanism of MS could elucidate these links further.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0395-0) contains supplementary material, which is available to authorized users.

DNA Methylation Signatures of a Large Cohort Monozygotic Twins Clinically Discordant for Multiple Sclerosis

“…Although in our data GC treatment history was not directly associated with global hypermethylation, we observed a significant association between increased within-pair ZBTB16 methylation differences and the number of hypermethylated CpGs in the MS-affected co-twins. This might indirectly indicate that GCs also affect global DNA methylation levels, which might also explain the strong repetitive element hypermethylation in MS patients reported by Neven et al 58 , who applied an inclusion criterion of only >1 month after GC treatment. Accordingly, additional studies are warranted to evaluate whether global hypermethylation in MS patients, observed by us and others 19,58,59 , is due to GC treatment history.…”

“…Neven et al 58 reported hypermethylation of the repetitive elements Alu, LINE1 and Sat-α in blood of MS patients compared to controls. Also Dunaeva et al 59 observed hypermethylation at a subset of LINE1 CpGs in serum cell-free DNA of RRMS patients.…”

Warning SINEs: Alu elements, evolution of the human brain, and the spectrum of neurological disease

“…Alu elements have played a pivotal role in the evolution of the human epigenome (Prendergast et al 2014 ), and both hypermethylation and hypomethylation of Alu elements have been correlated with a number of age-related disorders including Alzheimer’s disease, multiple sclerosis, osteoporosis, and many forms of cancer (Bollati et al 2009 ; Jintaridth and Mutirangura 2010 ; Belancio et al 2010 ; Jintaridth et al 2013 ; Neven et al 2016 ). In light of these patterns, as well as the newly discovered regulatory roles of Alu elements (Polak and Domany 2006 ; Chen and Carmichael 2008 ; Chen and Yang 2017 ), we recommend additional research that focuses on the epigenetic interplay between Alu elements and mitochondrial gene networks in the central nervous system.…”

“…1 ; Deininger and Batzer 1999 ; Deininger 2011 ; Tarallo et al 2012 ; Ade et al 2013 ; Elbarbary et al 2016 ; Varizhuk et al 2016 ). For this reason, the genome tightly regulates Alus using both DNA methylation and histone (H3K9 methylation) modification in order to control their expression and de novo retrotransposition (Varshney et al 2015 ; Elbarbary et al 2016 ; Mita and Boeke 2016 ), and there is mounting evidence indicating that the loss of these epigenetic control mechanisms (due to aging, cellular senescence, environmental factors, and stress) contributes to many forms of cancer, diabetes, osteoporosis, and several mental and neurodegenerative disorders (Szpakowski et al 2009 ; Belancio et al 2010 ; Muotri et al 2010 ; Jintaridth et al 2013 ; Dannlowski et al 2014 ; Erwin et al 2014 ; Bundo et al 2014 ; Sun et al 2014 ; Goodier 2016 ; Neven et al 2016 ; Bedrosian et al 2016 ; Shpyleva et al 2017 ; Thongsroy et al 2017 ). With respect to deleterious Alu pathways and neurological disease, there are at least 37 mental and neurodegenerative disorders wherein Alu elements are hypothesized to disrupt key cellular processes, thereby resulting in or contributing to the diseased state (Table 1 ).…”

LINE-1 Hypermethylation in Serum Cell-Free DNA of Relapsing Remitting Multiple Sclerosis Patients

“…A similar pattern of hypomethylation of LINE-1 repeats in CD4+, CD8+ T cells and B lymphocytes subsets from SLE patients in comparison with healthy controls was observed [ 23 ]. A recent study on methylation of repetitive elements demonstrated hypermethylation of repetitive elements (Alu, LINE-1, and SAT-a) in whole blood of MS patients compared to healthy controls [ 25 ]. Methylation levels of LINE-1 and Alu were correlated with EDSS scores.…”