Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA834633 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19050500_1.fastq.gz | Fastqsanger.gz | |||
| SRR19050500_2.fastq.gz | Fastqsanger.gz | |||
| SRR19050501_1.fastq.gz | Fastqsanger.gz | |||
| SRR19050501_2.fastq.gz | Fastqsanger.gz | |||
| SRR19050502_1.fastq.gz | Fastqsanger.gz |
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Project description:We have performed ATAC-seq from FACS sorted immune cell populations from peripheral blood of human donors. All donors have a diagnosis of multiple sclerosis and some donors were treated with immunotherapy (glatiramer acetate, interferon beta, or natalizumab). We called peaks from the ATAC-seq data and tested for enrichment of open chromatin regions for each cell population in MS GWAS.
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Project description:BackgroundMultiple sclerosis (MS) is an autoimmune condition of the central nervous system with a well-characterized genetic background. Prior analyses of MS genetics have identified broad enrichments across peripheral immune cells, yet the driver immune subsets are unclear.ResultsWe utilize chromatin accessibility data across hematopoietic cells to identify cell type-specific enrichments of MS genetic signals. We find that CD4 T and B cells are independently enriched for MS genetics and further refine the driver subsets to Th17 and memory B cells, respectively. We replicate our findings in data from untreated and treated MS patients and find that immunomodulatory treatments suppress chromatin accessibility at driver cell types. Integration of statistical fine-mapping and chromatin interactions nominate numerous putative causal genes, illustrating complex interplay between shared and cell-specific genes.ConclusionsOverall, our study finds that open chromatin regions in CD4 T cells and B cells independently drive MS genetic signals. Our study highlights how careful integration of genetics and epigenetics can provide fine-scale insights into causal cell types and nominate new genes and pathways for disease.
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Project description:Systemic sclerosis (SSc) shows complex clinical manifestations including progressive skin and internal organ fibrosis. SSc can be divided into 'intrinsic subsets' by gene expression suggesting patient-specific heterogeneity in pathogenesis or temporal evolution of disease. Here we validate these subsets using an independent patient population, and test whether the genes vary over time with patients changing subsets as disease progresses, or if the genes are a stable feature of the patients within each subset. Skin biopsies were analyzed from 13 dSSc patients enrolled in an open label study of rituximab, 9 dSSc patients not treated with rituximab, and 9 healthy controls. These data recapitulate the patient 'intrinsic subsets' described previously with gene expression associated with cell proliferation, inflammatory processes, and a normal-like group. Serial skin biopsies showed consistent and non-progressing gene expression. We were unable to detect significant differences in gene expression before and after rituximab treatment, consistent with an apparent lack of clinical response. Serial biopsies from each patient stayed within the same gene expression subset regardless of treatment regimen or the time point at which they were taken. This demonstrates the intrinsic subsets are an inherent, reproducible and stable feature of SSc that is independent of disease duration. Skin biopsies were analyzed from 13 dSSc patients enrolled in an open label study of rituximab, 9 dSSc patients not treated with rituximab, and 9 healthy controls.
2012-03-23 | E-GEOD-32413 | biostudies-arrayexpress
Project description:Systemic sclerosis (SSc) shows complex clinical manifestations including progressive skin and internal organ fibrosis. SSc can be divided into 'intrinsic subsets' by gene expression suggesting patient-specific heterogeneity in pathogenesis or temporal evolution of disease. Here we validate these subsets using an independent patient population, and test whether the genes vary over time with patients changing subsets as disease progresses, or if the genes are a stable feature of the patients within each subset. Skin biopsies were analyzed from 13 dSSc patients enrolled in an open label study of rituximab, 9 dSSc patients not treated with rituximab, and 9 healthy controls. These data recapitulate the patient 'intrinsic subsets' described previously with gene expression associated with cell proliferation, inflammatory processes, and a normal-like group. Serial skin biopsies showed consistent and non-progressing gene expression. We were unable to detect significant differences in gene expression before and after rituximab treatment, consistent with an apparent lack of clinical response. Serial biopsies from each patient stayed within the same gene expression subset regardless of treatment regimen or the time point at which they were taken. This demonstrates the intrinsic subsets are an inherent, reproducible and stable feature of SSc that is independent of disease duration.
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Project description:Genome-wide profiling of epigenomic marks allows rapid prediction of transcriptional regulatory regions, including promoters and enhancers. However, experimental validation of predicted regions’ effect on gene expression, and high-resolution dissection of driver sequence elements within them, have remained infeasible on a high throughput scale. Here, we describe HiDRA (High-Definition Reporter Assay), a high-throughput episomal assay for the high-resolution dissection of promoter and enhancer activity genome-wide. We applied HiDRA on millions of DNA fragments preferentially extracted from open chromatin. We applied HiDRA to the GM12878 lymphoblastoid cell line, generating a 6.83 million fragment library preferentially extracted from open chromatin, and revealed tens of thousands of genomic regions that significantly drive reporter gene transcription. These regions are enriched for H3K9ac, H3K27ac, other active histone marks, known regulatory motifs, and regions bound by immune regulators. We developed a new algorithm, SHARPR2, to deconvolve fragment-level activity measurements from regulatory regions tiled by dozens to hundreds of offset fragments to enable high-resolution maps of activity patterns, pinpointing individual driver regulatory motifs and predicting driver genetic variants underlying immune diseases. Our results indicate that HiDRA provides a general and scalable high-throughput and high-resolution strategy for experimental dissection of regulatory regions and nucleotides in the context of human biology and disease.
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Project description:Pathway expression analysis in systemic sclerosis revealed key mediators driving pathology within each of the intrinsic gene expression subsets. Genome-wide expression profiling in systemic sclerosis (SSc) has identified four 'intrinsic' subsets of disease (fibroproliferative, inflammatory, limited, and normal-like), each of which appear to be driven by distinct signaling pathways. Here we examine experimentally derived gene expression signatures for thirteen agonists to better understand the molecular mechanisms underlying each intrinsic subsets. Pathway-specific gene signatures were compared against skin biopsy microarray data consisting of 329 microarray hybridizations from 287 unique biopsies representing 111 patients. Hierarchical clustering recapitulated the four SSc 'intrinsic' gene expression subsets, along with an intermediate subset exhibiting both inflammatory and fibroproliferative gene expression signatures. The fibroproliferative subset is most strongly associated with the PDGF gene signature, while the inflammatory subset demonstrated strong activation of NF-kappaB, characterized by early induction of TH2 signals, which transitions to a more TH17-like immune response over time. The limited subset was associated with IFNalpha signaling, combined with strong downregulation of PDGF signaling. The inflammatory-proliferative subset shows downregulation of NF-kappaB-associated pathways in conjunction with increased PDGF signaling, suggestive of a transitional state linking the inflammatory and fibroproliferative subsets. IL-13 signaling was strongly associated with early disease, while TGFbeta signaling was associated with more severe disease. Together these data suggest a multi-step, progressive model of disease pathogenesis driven by distinct pathways. Targeting these pathways based upon a patient's underlying disease subset should improve therapeutic outcomes. In vitro treatment of human dermal fibroblasts was performed to identify pathway-specific gene signatures. These gene signatures were then compared against systemic sclerosis skin biopsy microarrays to determine the overall contribution of each pathway to disease. This study includes re-analysis of 247 skin biopsy samples from GSE9285, GSE32413, and GSE45485. Links to these Samples are provided below. The re-processed normalized data for these Samples are included in the supplementary file 'GSE56308_247_Skin_Biopsy_Reanalysis_Samples.txt'.
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