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Series GSE137143 Query DataSets for GSE137143
Status Public on Dec 31, 2020
Title Cell-Type-Specific Transcriptome of CD4+, CD8+ T cells and CD14+ monocytes in multiple sclerosis
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Multiple sclerosis (MS) is an autoimmune disease of the central nervous system in which both genetic and environmental factors are thought to be involved. Genome-wide association studies revealed more than 200 risk loci, most of which harbor genes primarily expressed in immune cells. However, whether genetic differences are translated into cell-specific gene expression profiles and to what extent these are altered in MS are not well understood. To assess cell-type-specific gene expression in a large cohort of MS patients, we sequenced the whole transcriptome of sorted T cells (CD4+ and CD8+) and CD14+ monocytes from treatment-naive MS patients (n=122) and healthy subjects (n=22). Next, we performed a comprehensive analysis of the RNA sequencing dataset and identified 612 differentially expressed genes (DEGs) in CD14+ monocytes, 464 in CD4+ T cells, and 93 in CD8+ T cells. Notably, about one third (36.6%) of DEGs were non-coding RNAs, the majority of which (88.2%) were down-regulated in MS. We identified large co-expressed gene modules and cis-eQTLs with key MS genes in each cell subset. Importantly, we discovered dysregulation of NAE1, a subunit of NEDD8 activating enzyme (NAE), in CD4+ T cells which activates the neddylation pathway. Finally, we demonstrated that NAE inhibition using Pevonedistat (MLN4924) dampened disease severity in murine experimental autoimmune encephalomyelitis (EAE). Our findings provide novel insights into MS-associated gene regulation unraveling neddylation as a crucial pathway in MS pathogenesis with implications for the development of tailored disease-modifying agents.
 
Overall design Whole transcriptome profile of sorted CD4+ T cells, CD8+ T cells, and CD14+ monocytes in treatment naïve MS patients (n=122) and healthy controls (n=22)
Web link https://academic.oup.com/brain/article-abstract/144/2/450/6055080
 
Contributor(s) Kim K, Baranzini SE
Citation(s) 33374005
NIH grant(s)
Grant ID Grant title Affiliation Name
R01 NS088155 Post GWAS approach to identify cell-specific genetic pathways underlying MS risk University of California San Francisco SERGIO E BARANZINI
Submission date Sep 09, 2019
Last update date Sep 23, 2021
Contact name Sergio E Baranzini
E-mail(s) Sergio.Baranzini@ucsf.edu
Phone (415) 502-6865
Organization name UCSF
Department Neurology
Lab Baranzini Lab.
Street address 675 Nelson Rising LN, STE 240
City San Francisco
State/province CA
ZIP/Postal code 94158
Country USA
 
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (427)
GSM4071521 Healthy controls, 13311d-CD14
GSM4071522 Healthy controls, 13311d-CD4
GSM4071523 Healthy controls, 13311d-CD8
Relations
BioProject PRJNA564629
SRA SRP221152

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE137143_RAW.tar 1.1 Gb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file
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