Proximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome

AbstractIdentifying the effects of genetic variation on the epigenome in disease-relevant cell types can help advance our understanding of the first molecular contributions of genetic susceptibility to disease onset. Here, we establish a genome-wide map of DNA methylation quantitative trait loci in CD4+ T-cells isolated from multiple sclerosis patients. Utilizing this map in a colocalization analysis, we identify 19 loci where the same haplotype drives both multiple sclerosis susceptibility and local DNA methylation. We also identify two distant methylation effects of multiple sclerosis susceptibility loci: a chromosome 16 locus affects PRDM8 methylation (a chromosome 4 region not previously associated with multiple sclerosis), and the aggregate effect of multiple sclerosis-associated variants in the major histocompatibility complex influences DNA methylation near PRKCA (chromosome 17). Overall, we present a new resource for a key cell type in inflammatory disease research and uncover new gene targets for the study of predisposition to multiple sclerosis.

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Impact of genetic susceptibility to multiple sclerosis on the T cell epigenome: proximal and distal effects

10.1101/2020.07.11.198721 ◽

2020 ◽

Author(s):

Tina Roostaei ◽

Hans-Ulrich Klein ◽

Daniel Felsky ◽

Pia Kivisäkk ◽

Sarah M. Connor ◽

...

Keyword(s):

Multiple Sclerosis ◽

Dna Methylation ◽

Chromosome 17 ◽

Gene Target ◽

Risk Alleles ◽

A Genome ◽

Functional Consequences ◽

New Gene ◽

Aggregate Effect ◽

Trait Locus

ABSTRACTWe establish a genome-wide map of DNA methylation quantitative trait locus (mQTL) effects in CD4+ T cells isolated from multiple sclerosis (MS) patients. Utilizing this map in a colocalization analysis, we identify 19 loci where the same haplotype drives both MS susceptibility and local (cis-) DNA methylation. We also identify two distant (trans-) mQTL effects of MS susceptibility loci: (1) a chromosome 16 MS locus affects PRDM8 methylation (a chromosome 4 region not previously associated with MS susceptibility), and (2) the aggregate effect of MS variants in the major histocompatibility complex (MHC, chromosome 6) influences DNA methylation near PRKCA on chromosome 17. Both effects are replicated in independent samples. Overall, we present a new methylome-wide mQTL resource for a key cell type in inflammatory disease research, uncover functional consequences of MS susceptibility variants, including the convergence of MHC risk alleles onto a new gene target involved in predisposition to MS.

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Epigenetic modifications in brain and immune cells of multiple sclerosis patients

Multiple Sclerosis Journal ◽

10.1177/1352458517737389 ◽

2018 ◽

Vol 24 (1) ◽

pp. 69-74 ◽

Cited By ~ 12

Author(s):

Kamilah Castro ◽

Patrizia Casaccia

Keyword(s):

Multiple Sclerosis ◽

Dna Methylation ◽

Histone Acetylation ◽

Cell Function ◽

Cell Types ◽

Epigenetic Modifications ◽

Post Translational Modification ◽

Inflammatory Phenotype ◽

Cellular Specificity ◽

Multiple Sclerosis Patients

Multiple sclerosis (MS) is a debilitating neurological disease whose onset and progression are influenced by the interplay of genetic and environmental factors. Epigenetic modifications, which include post-translational modification of the histones and DNA, are considered mediators of gene–environment interactions and a growing body of evidence suggests that they play an important role in MS pathology and could be potential therapeutic targets. Since epigenetic events regulate transcription of different genes in a cell type–specific fashion, we caution on the distinct functional consequences that targeting the same epigenetic modifications might have in distinct cell types. In this review, we primarily focus on the role of histone acetylation and DNA methylation on oligodendrocyte and T-cell function and its potential implications for MS. We find that decreased histone acetylation and increased DNA methylation in oligodendrocyte lineage (OL) cells enhance myelin repair, which is beneficial for MS, while the same epigenetic processes in T cells augment their pro-inflammatory phenotype, which can exacerbate disease severity. In conclusion, epigenetic-based therapies for MS may have great value but only when cellular specificity is taken into consideration.

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DNA methylation changes in glial cells of the normal-appearing white matter in Multiple Sclerosis patients

10.1101/2021.06.21.21258936 ◽

2021 ◽

Author(s):

Lara Kular ◽

Ewoud Ewing ◽

Maria Needhamsen ◽

Majid Pahlevan Kakhki ◽

Ruxandra Covacu ◽

...

Keyword(s):

Multiple Sclerosis ◽

Dna Methylation ◽

White Matter ◽

Glial Cells ◽

Treatment Options ◽

Cell Types ◽

P Value ◽

Epigenetic Mark ◽

Normal Appearing White Matter ◽

Multiple Sclerosis Patients

Background Multiple Sclerosis (MS), the leading cause of non-traumatic neurological disability in young adults, is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). Due to the poor accessibility to the target organ, CNS-confined processes underpinning the later progressive form of MS remain elusive thereby limiting treatment options. We aim to examine DNA methylation, a stable epigenetic mark of genome activity, in glial cells to capture relevant molecular changes underlying MS neuropathology. Methods We profiled DNA methylation in nuclei of glial cells, isolated from 38 post-mortem normal-appearing white matter (NAWM) specimens of MS patients (n=8) in comparison to white matter of control individuals (n=14), using Infinium MethylationEPIC BeadChip. Findings We identified 1,226 significant (genome-wide adjusted P-value < 0.05) differentially methylated positions (DMPs) between MS patients and controls. Functional annotation of the altered DMP-genes uncovered alterations of processes related to cellular motility, cytoskeleton dynamics, metabolic processes, synaptic support, neuroinflammation and signaling, such as Wnt and TGF-β pathways. A fraction of the affected genes displayed transcriptional differences in the brain of MS patients, as reported by publically available transcriptomic data. Cell type-restricted annotation of DMP-genes attributed alteration of cytoskeleton rearrangement and extracellular matrix remodelling to all glial cell types, while some processes, including ion transport, Wnt/TGF-β signaling and immune processes were more specifically linked to oligodendrocytes, astrocytes and microglial cells, respectively. Conclusion Our findings strongly suggest that NAWM glial cells are highly altered, even in the absence of lesional insult, collectively exhibiting a multicellular reaction in response to diffuse inflammation.

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Cervical spinal cord volume and diffuse spinal cord abnormalities distinguish multiple sclerosis patients with different levels of disability already 5 years after disease onset

10.26226/morressier.59a3eda6d462b8028d894cf0 ◽

2017 ◽

Author(s):

Michalea Andelova

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Cervical Spinal Cord ◽

Disease Onset ◽

Multiple Sclerosis Patients ◽

Different Levels ◽

Spinal Cord Volume

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Genome-wide DNA methylation changes in CD19+ B cells from relapsing-remitting multiple sclerosis patients

Scientific Reports ◽

10.1038/s41598-018-35603-0 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 10

Author(s):

Vicki E. Maltby ◽

Rodney A. Lea ◽

Moira C. Graves ◽

Katherine A. Sanders ◽

Miles C. Benton ◽

...

Keyword(s):

Multiple Sclerosis ◽

Dna Methylation ◽

B Cells ◽

Genome Wide ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Multiple Sclerosis Patients ◽

Relapsing Remitting Multiple Sclerosis

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GSDMA drives the most replicated association with asthma in naïve CD4+ T cells

10.1101/774760 ◽

2019 ◽

Cited By ~ 1

Author(s):

Anne-Marie Madore ◽

Lucile Pain ◽

Anne-Marie Boucher-Lafleur ◽

Jolyane Meloche ◽

Andréanne Morin ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

T Cells ◽

Genetic Variants ◽

Immune Cell ◽

Cell Types ◽

Sequencing Data ◽

Opposite Pattern ◽

Genetic Mechanisms ◽

New Gene

AbstractBackgroundThe 17q12-21 locus is the most replicated association with asthma. However, no study had described the genetic mechanisms underlying this association considering all genes of the locus in immune cell samples isolated from asthmatic and non-asthmatic individuals.ObjectiveThis study takes benefit of samples from naïve CD4+ T cells and eosinophils isolated from the same 200 individuals to describe specific interactions between genetic variants, gene expression and DNA methylation levels for the 17q12-21 asthma locus.Methods and ResultsAfter isolation of naïve CD4+ T cells and eosinophils from blood samples, next generation sequencing was used to measure DNA methylation levels and gene expression counts. Genetic interactions were then evaluated considering genetic variants from imputed genotype data. In naïve CD4+ T cells but not eosinophils, 20 SNPs in the fourth and fifth haplotype blocks modulated both GSDMA expression and methylation levels, showing an opposite pattern of allele frequencies and expression counts in asthmatics compared to controls. Moreover, negative correlations have been measured between methylation levels of CpG sites located within the 1.5 kb region from the transcription start site of GSDMA and its expression counts.ConclusionAvailability of sequencing data from two key cell types isolated from asthmatic and non-asthmatic individuals allowed identifying a new gene in naïve CD4+ T cells that drives the association with the 17q12-21 locus, leading to a better understanding of the genetic mechanisms taking place in it.

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