Methylation patterns of cell-free plasma DNA in relapsing–remitting multiple sclerosis (original) (raw)
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Methylation-dependentPAD2upregulation in multiple sclerosis peripheral blood
Multiple Sclerosis Journal, 2011
Background: Peptidylarginine deiminase 2 (PAD2) and peptidylarginine deiminase 4 (PAD4) are two members of PAD family which are over-expressed in the multiple sclerosis (MS) brain. Through its enzymatic activity PAD2 converts myelin basic protein (MBP) arginines into citrullines-an event that may favour autoimmunity-while peptidylarginine deiminase 4 (PAD4) is involved in chromatin remodelling. Objectives: Our aim was to verify whether an altered epigenetic control of PAD2, as already shown in the MS brain, can be observed in peripheral blood mononuclear cells (PBMCs) of patients with MS since some of these cells also synthesize MBP. Methods: The expression of most suitable reference genes and of PAD2 and PAD4 was assessed by qPCR. Analysis of DNA methylation was performed by bisulfite method. Results: The comparison of PAD2 expression level in PBMCs from patients with MS vs. healthy donors showed that, as well as in the white matter of MS patients, the enzyme is significantly upregulated in affected subjects. Methylation pattern analysis of a CpG island located in the PAD2 promoter showed that over-expression is associated with promoter demethylation. Conclusion: Defective regulation of PAD2 in the periphery, without the immunological shelter of the blood-brain barrier, may contribute to the development of the autoimmune responses in MS.
Serum DNA Motifs Predict Disease and Clinical Status in Multiple Sclerosis
The Journal of Molecular Diagnostics, 2010
Using recently available mass sequencing and assembly technologies , we have been able to identify and quantify unique cell-free DNA motifs in the blood of patients with multiple sclerosis (MS). The most common MS clinical syndrome , relapsing-remitting MS (RRMS) , is accompanied by a unique fingerprint of both inter-and intragenic cell-free circulating nucleic acids as specific DNA sequences that provide significant clinical sensitivity and specificity. Coding genes that are differentially represented in MS serum encode cytoskeletal proteins, brain-expressed regulators of growth, and receptors involved in nervous system signal transduction. Although coding genes distinguish RRMS and its clinical activity, several repeat sequences, such as the L1M family of LINE elements, are consistently different in all MS patients and clinical status versus the normal database. These data demonstrate that DNA motifs observed in serum are characteristic of RRMS and disease activity and are promising as a clinical tool in monitoring patient responses to treatment modalities
The Internet journal of neurology, 2010
Objective: To study if differences in gene expression in brain tissue among African-Americans (AA) and Caucasian Americans (CA) with multiple sclerosis (MS) exist. Understanding any genetic differences is critical for better understanding of MS and its outcomes.Methods: Microarray and microRNA methods were used in chronic brain lesions of AA and CA patients with MS.Results: We found marked downregulation in GM2A (5.2 vs. 2.07), GALC (4.48 vs. 2.66), EIF1AY (4.54 vs. 1.57) and carboxypeptidase D (3.72 vs. 1.79), genes among chronic lesions taken from AA and CA brains and validated using real-time qPCR techniques. A total of 1108 genes were down regulated, compared to 467 genes that were upregulated in chronic MS lesions, compared to normal appearing brain matter (ratio of 2:1); a similar comparison between AA and CA brains revealed a total of 611 down regulated vs. 192 upregulated genes (ratio of 3:1). Interpretation: Significant downregulation of GM2A, GALC, EIF1AY and carboxypeptidase D in the AA lesions as compared to CA cohort could have implications for MS.
Deciphering the role of DNA methylation in multiple sclerosis: emerging issues
Auto- immunity highlights, 2016
Multiple sclerosis (MS) is an autoimmune inflammatory and neurodegenerative disease of the central nervous system that involves several not yet fully elucidated pathophysiologic mechanisms. There is increasing evidence that epigenetic modifications at level of DNA bases, histones, and micro-RNAs may confer risk for MS. DNA methylation seems to have a prominent role in the epigenetics of MS, as aberrant methylation in the promoter regions across genome may underlie several processes involved in the initiation and development of MS. In the present review, we discuss current understanding regarding the role of DNA methylation in MS, possible therapeutic implications and future emerging issues.
CpG Island Methylation Patterns in Relapsing-Remitting Multiple Sclerosis
Journal of molecular neuroscience : MN, 2018
DNA methylation may predispose to multiple sclerosis (MS), as aberrant methylation in the promoter regions across the genome seems to underlie several processes of MS. We have currently determined the methylation status of eight genes in relapsing-remitting MS patients. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was used to determine the status of 31 CpG islands, located across eight genes, in 33 healthy individuals and 66 MS patients (33 in relapse and 33 in remission). The methylation levels in the examined sites ranged from 0 to 31%. Methylation positivity for RUNX3 and CDKN2A differed significantly between MS patients and healthy controls. Maximum methylation in RUNX3, CDKN2A, SOCS1, and NEUROG1 genes was significantly different between patients and controls. Roc curves demonstrated that the appropriate cut-offs to distinguish patients from healthy controls were 2% for RUNX3 (OR 3.316, CI 1.207-9.107, p = 0.024) and 3% for CDKN2A (OR 3.077, C...
Methylation-dependent PAD2 upregulation in multiple sclerosis peripheral blood
Multiple Sclerosis Journal, 2011
Background: Peptidylarginine deiminase 2 (PAD2) and peptidylarginine deiminase 4 (PAD4) are two members of PAD family which are over-expressed in the multiple sclerosis (MS) brain. Through its enzymatic activity PAD2 converts myelin basic protein (MBP) arginines into citrullines – an event that may favour autoimmunity – while peptidylarginine deiminase 4 (PAD4) is involved in chromatin remodelling. Objectives: Our aim was to verify whether an altered epigenetic control of PAD2, as already shown in the MS brain, can be observed in peripheral blood mononuclear cells (PBMCs) of patients with MS since some of these cells also synthesize MBP. Methods: The expression of most suitable reference genes and of PAD2 and PAD4 was assessed by qPCR. Analysis of DNA methylation was performed by bisulfite method. Results: The comparison of PAD2 expression level in PBMCs from patients with MS vs. healthy donors showed that, as well as in the white matter of MS patients, the enzyme is significantly u...
Biomarkers of multiple sclerosis: current findings
Degenerative Neurological and Neuromuscular Disease
Multiple sclerosis (MS) is an autoimmune disease affecting the brain and spinal cord that is associated with chronic inflammation leading to demyelination and neurodegeneration. With the recent increase in the number of available therapies for MS, optimal treatment will be based on a personalized approach determined by an individual patient's prognosis and treatment risks. An integral part of such therapeutic decisions will be the use of molecular biomarkers to predict disability progression, monitor ongoing disease activity, and assess treatment response. This review describes current published findings within the past 3 years in biomarker research in MS, specifically highlighting recent advances in the validation of cerebrospinal fluid biomarkers such as neurofilaments (light and heavy chains), chitinases and chitinase 3-like proteins, soluble surface markers of innate immunity, and oligoclonal immunoglobulin M antibodies. Current research in circulating miRNAs as biomarkers of MS is also discussed. Continued validation and testing will be required before MS biomarkers are routinely applied in a clinical setting.