Deep characterization of paired chromatin and transcriptomes in four immune cell types from multiple sclerosis patients

Epigenomics ◽  
2021 ◽  
Author(s):  
Sunjay Jude Fernandes ◽  
Matilda Ericsson ◽  
Mohsen Khademi ◽  
Maja Jagodic ◽  
Tomas Olsson ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Cell ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Primary Role ◽  
Nucleotide Polymorphisms ◽  
Multiple Sclerosis Patients ◽  
Accessible Chromatin

Background: The putative involvement of chromatin states in multiple sclerosis (MS) is thus far unclear. Here we determined the association of chromatin-accessibility with concurrent genetic, epigenetic and transcriptional events. Material & methods: We generated paired assay for transposase-accessible chromatin sequencing and RNA-seq profiles from sorted blood immune CD4+ and CD8+ T cells, CD14+ monocytes and CD19+ B cells from healthy controls (HCs) and MS patients. Results: We identified differentially accessible regions between MS and HCs, primarily in CD4+ and CD19+. CD4+ regions were enriched for MS-associated single nucleotide polymorphisms and differentially methylated loci. In the vicinity of differentially accessible regions of CD4+ cells, 42 differentially expressed genes were identified. The top two dysregulated genes identified in this multilayer analysis were CCDC114 and SERTAD1. Conclusion: These findings provide new insight into the primary role of CD4+ and CD19+ cells in MS.

CD46 in a Spanish cohort of multiple sclerosis patients: genetics, mRNA expression and response to interferon-beta treatment

2010 ◽  
Vol 17 (5) ◽  
pp. 513-520 ◽  
Author(s):  
Roberto Alvarez-Lafuente ◽  
Fiona Blanco-Kelly ◽  
Marta Garcia-Montojo ◽  
Alfonso Martínez ◽  
Virginia De Las Heras ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mrna Expression ◽  
Interferon Beta ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Multiple Sclerosis Patients ◽  
Spanish Cohort ◽  
Independent Cohort

Background: In a prior study of our group we found an up-regulation of CD46 expression in a cohort of Spanish multiple sclerosis (MS) patients. Objective: To evaluate the potential role of CD46 in the response to interferon-beta treatment in MS patients through the analysis of five tagging single nucleotide polymorphisms (SNPs) and measurement of mRNA. Methods: A total of 406 MS patients and 513 control patients were analysed for five SNPs at the CD46 locus. Furthermore, 163 MS patients and 163 matched control patients were analysed by RT-PCR for the CD46 mRNA expression in three blood samples (basal, and at 6 and 12 months of interferon-beta treatment) collected in the course of a 1-year follow-up. Results: Two genotypes of rs2724385 polymorphism (AT and TT) could be markers of response to interferon-beta therapy in MS patients ( p = 0.007 and p = 0.006, respectively). Furthermore, the frequency of interferon-beta responders was 44.4% (32/72) in MS patients with an increased CD46 mRNA expression, vs. 65.9% (60/91) in patients with a decreased CD46 mRNA expression ( p = 0.006). Conclusion: The present study shows that CD46 could be associated with the response to interferon-beta therapy; however, the genetic results should be replicated in an independent cohort and further studies are needed to confirm the role of CD46.

scholarly journals The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1280 ◽  
Author(s):  
Alessandro Maglione ◽  
Simona Rolla ◽  
Stefania Federica De Mercanti ◽  
Santina Cutrupi ◽  
Marinella Clerico
Keyword(s):  
Multiple Sclerosis ◽  
Immune System ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Adaptive Immune System ◽  
Cell Types ◽  
Point Of View ◽  
Adaptive Immune ◽  
Future Path

Multiple sclerosis (MS) is a chronic central nervous system inflammatory disease that leads to demyelination and neurodegeneration. The third trimester of pregnancy, which is characterized by high levels of estrogens, has been shown to be associated with reduced relapse rates compared with the rates before pregnancy. These effects could be related to the anti-inflammatory properties of estrogens, which orchestrate the reshuffling of the immune system toward immunotolerance to allow for fetal growth. The action of these hormones is mediated by the transcriptional regulation activity of estrogen receptors (ERs). Estrogen levels and ER expression define a specific balance of immune cell types. In this review, we explore the role of estradiol (E2) and ERs in the adaptive immune system, with a focus on estrogen-mediated cellular, molecular, and epigenetic mechanisms related to immune tolerance and neuroprotection in MS. The epigenome dynamics of immune systems are described as key molecular mechanisms that act on the regulation of immune cell identity. This is a completely unexplored field, suggesting a future path for more extensive research on estrogen-induced coregulatory complexes and molecular circuitry as targets for therapeutics in MS.

Strains of Epstein-Barr virus infecting multiple sclerosis patients

2010 ◽  
Vol 16 (6) ◽  
pp. 643-651 ◽  
Author(s):  
RM Brennan ◽  
JM Burrows ◽  
MJ Bell ◽  
L. Bromham ◽  
PA Csurhes ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Epstein Barr Virus ◽  
Experimental Studies ◽  
Nucleotide Polymorphisms ◽  
Barr Virus ◽  
Genes Encoding ◽  
Epstein Barr ◽  
Multiple Sclerosis Patients ◽  
Ebna1 Gene

Both epidemiological and experimental studies have indicated that the ubiquitous herpesvirus Epstein—Barr virus (EBV) plays a role in the pathogenesis of multiple sclerosis (MS). Some features of MS epidemiology, such as the decline in risk among migrants from high to low MS prevalence areas, suggest the presence of variant EBV strains that increase MS risk. The objective of this study was to investigate whether genetic variability in EBV is associated with MS. Genes encoding for two EBV antigens (EBNA1 and BRRF2) were sequenced in EBV isolates from 40 MS patients and a similar number of control subjects. These viral antigens were chosen for analysis because they are known to stimulate atypical immune responses in MS. Extensive sequence polymorphism was observed within the EBNA1 and BRRF2 genes in isolates from both MS patients and controls. Interestingly, several single nucleotide polymorphisms within the EBNA1 gene, and one within the BRRF2 gene, were found to occur at marginally different frequencies in EBV strains infecting MS patients versus controls. Although this study does not find a simple causal relationship between EBV strains and the occurrence of MS, the existence of haplotypes that occur at different frequencies in MS patients versus controls may provide an area for future study of the role of EBV strain variation in multiple sclerosis.

scholarly journals Landscape of stimulation-responsive chromatin across diverse human immune cells

2018 ◽  
Author(s):  
Diego Calderon ◽  
Michelle L. T. Nguyen ◽  
Anja Mezger ◽  
Arwa Kathiria ◽  
Vinh Nguyen ◽  
...  
Keyword(s):  
Large Scale ◽  
Immune Cell ◽  
Gene Expression Regulation ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Distinct Cell ◽  
Significant Heritability ◽  
Allele Specific ◽  
Scale Characterization

AbstractThe immune system is controlled by a balanced interplay among specialized cell types transitioning between resting and stimulated states. Despite its importance, the regulatory landscape of this system has not yet been fully characterized. To address this gap, we collected ATAC-seq and RNA-seq data under resting and stimulated conditions for 25 immune cell types from peripheral blood of four healthy individuals, and seven cell types from three fetal thymus samples. We found that stimulation caused widespread chromatin remodeling, including a large class of response elements shared between stimulated B and T cells. Furthermore, several autoimmune traits showed significant heritability in stimulation-responsive elements from distinct cell types, highlighting the critical importance of these cell states in autoimmunity. Use of allele-specific read-mapping identified thousands of variants that alter chromatin accessibility in particular conditions. Notably, variants associated with changes in stimulation-specific chromatin accessibility were not enriched for associations with gene expression regulation in whole blood – a tissue commonly used in eQTL studies. Thus, large-scale maps of variants associated with gene regulation lack a condition important for understanding autoimmunity. As a proof-of-principle we identified variant rs6927172, which links stimulated T cell-specific chromatin dysregulation in the TNFAIP3 locus to ulcerative colitis and rheumatoid arthritis. Overall, our results provide a broad resource of chromatin landscape dynamics and highlight the need for large-scale characterization of effects of genetic variation in stimulated cells.

scholarly journals A rapid and robust method for single cell chromatin accessibility profiling

2018 ◽  
Author(s):  
Xi Chen ◽  
Ricardo J Miragaia ◽  
Kedar Nath Natarajan ◽  
Sarah A Teichmann
Keyword(s):  
Single Cell ◽  
Immune Cell ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Single Cell Level ◽  
Cell Type ◽  
Cell Level ◽  
Regulatory Regions ◽  
Cell Type Specific ◽  
Accessible Chromatin

AbstractThe assay for transposase-accessible chromatin using sequencing (ATAC-seq) is widely used to identify regulatory regions throughout the genome. However, very few studies have been performed at the single cell level (scATAC-seq) due to technical challenges. Here we developed a simple and robust plate-based scATAC-seq method, combining upfront bulk Tn5 tagging with single-nuclei sorting. We demonstrated that our method worked robustly across various systems, including fresh and cryopreserved cells from primary tissues. By profiling over 3,000 splenocytes, we identify distinct immune cell types and reveal cell type-specific regulatory regions and related transcription factors.

scholarly journals Biological characteristics of transcription factor RelB in different immune cell types: implications for the treatment of multiple sclerosis

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Meng-ge Yang ◽  
Li Sun ◽  
Jinming Han ◽  
Chao Zheng ◽  
Hudong Liang ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Dendritic Cells ◽  
Transcription Factor ◽  
Immune Cell ◽  
Demyelinating Disease ◽  
Cell Types ◽  
Lymphoid Organ ◽  
Therapeutic Implications

AbstractTranscription factor RelB is a member of the nuclear factror-kappa B (NF-κB) family, which plays a crucial role in mediating immune responses. Plenty of studies have demonstrated that RelB actively contributes to lymphoid organ development, dendritic cells maturation and function and T cells differentiation, as well as B cell development and survival. RelB deficiency may cause a variety of immunological disorders in both mice and humans. Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system which involves a board of immune cell populations. Thereby, RelB may exert an impact on MS by modulating the functions of dendritic cells and the differentiation of T cells and B cells. Despite intensive research, the role of RelB in MS and its animal model, experimental autoimmune encephalomyelitis, is still unclear. Herein, we give an overview of the biological characters of RelB, summarize the updated knowledge regarding the role of RelB in different cell types that contribute to MS pathogenesis and discuss the potential RelB-targeted therapeutic implications for MS.

scholarly journals Multiple sclerosis risk variants regulate gene expression in innate and adaptive immune cells

2020 ◽  
Vol 3 (7) ◽  
pp. e202000650 ◽  
Author(s):  
Melissa M Gresle ◽  
Margaret A Jordan ◽  
Jim Stankovich ◽  
Tim Spelman ◽  
Laura J Johnson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
Quantitative Trait Loci ◽  
Quantitative Trait ◽  
Immune Cell ◽  
Cell Types ◽  
Expression Quantitative Trait Loci ◽  
Nucleotide Polymorphisms ◽  
Adaptive Immune Cells ◽  
Trait Loci

At least 200 single-nucleotide polymorphisms (SNPs) are associated with multiple sclerosis (MS) risk. A key function that could mediate SNP-encoded MS risk is their regulatory effects on gene expression. We performed microarrays using RNA extracted from purified immune cell types from 73 untreated MS cases and 97 healthy controls and then performed Cis expression quantitative trait loci mapping studies using additive linear models. We describe MS risk expression quantitative trait loci associations for 129 distinct genes. By extending these models to include an interaction term between genotype and phenotype, we identify MS risk SNPs with opposing effects on gene expression in cases compared with controls, namely, rs2256814 MYT1 in CD4 cells (q = 0.05) and rs12087340 RF00136 in monocyte cells (q = 0.04). The rs703842 SNP was also associated with a differential effect size on the expression of the METTL21B gene in CD8 cells of MS cases relative to controls (q = 0.03). Our study provides a detailed map of MS risk loci that function by regulating gene expression in cell types relevant to MS.

scholarly journals Four Mutant Alleles Elucidate the Role of the G2 Protein in the Development of C4 and C3 Photosynthesizing Maize Tissues

Genetics ◽  
2001 ◽  
Vol 159 (2) ◽  
pp. 787-797
Author(s):  
Lizzie Cribb ◽  
Lisa N Hall ◽  
Jane A Langdale
Keyword(s):  
Cell Types ◽  
Bundle Sheath ◽  
Primary Role ◽  
Ribulose Bisphosphate Carboxylase ◽  
Sheath Cell ◽  
Mesophyll Cells ◽  
Phenotypic Data ◽  
Bisphosphate Carboxylase ◽  
Bundle Sheath Cell

Abstract Maize leaf blades differentiate dimorphic photosynthetic cell types, the bundle sheath and mesophyll, between which the reactions of C4 photosynthesis are partitioned. Leaf-like organs of maize such as husk leaves, however, develop a C3 pattern of differentiation whereby ribulose bisphosphate carboxylase (RuBPCase) accumulates in all photosynthetic cell types. The Golden2 (G2) gene has previously been shown to play a role in bundle sheath cell differentiation in C4 leaf blades and to play a less well-defined role in C3 maize tissues. To further analyze G2 gene function in maize, four g2 mutations have been characterized. Three of these mutations were induced by the transposable element Spm. In g2-bsd1-m1 and g2-bsd1-s1, the element is inserted in the second intron and in g2-pg14 the element is inserted in the promoter. In the fourth case, g2-R, four amino acid changes and premature polyadenylation of the G2 transcript are observed. The phenotypes conditioned by these four mutations demonstrate that the primary role of G2 in C4 leaf blades is to promote bundle sheath cell chloroplast development. C4 photosynthetic enzymes can accumulate in both bundle sheath and mesophyll cells in the absence of G2. In C3 tissue, however, G2 influences both chloroplast differentiation and photosynthetic enzyme accumulation patterns. On the basis of the phenotypic data obtained, a model that postulates how G2 acts to facilitate C4 and C3 patterns of tissue development is proposed.

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