期刊
CELL
卷 181, 期 2, 页码 382-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2020.03.002
关键词
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资金
- NIH [5DP1DA044337, R01 NS096148, R35 NS097303]
- National Multiple Sclerosis Society [RG-1701-26707]
- Euro-pean Union's Seventh Framework Programme (FP7/2007-2013) [282510 BLUEPRINT]
- Wellcome Trust [076113]
Multiple sclerosis (MS) is an autoimmune disease characterized by attack on oligodendrocytes within the central nervous system (CNS). Despite widespread use of immunomodulatory therapies, patients may still face progressive disability because of failure of myelin regeneration and loss of neurons, suggesting additional cellular pathologies. Here, we describe a general approach for identifying specific cell types in which a disease allele exerts a pathogenic effect. Applying this approach to MS risk loci, we pinpoint likely pathogenic cell types for 70%. In addition to T cell loci, we unexpectedly identified myeloid- and CNS-specific risk loci, including two sites that dysregulate transcriptional pause release in oligodendrocytes. Functional studies demonstrated inhibition of transcriptional elongation is a dominant pathway blocking oligodendrocyte maturation. Furthermore, pause release factors are frequently dysregulated in MS brain tissue. These data implicate cell-intrinsic aberrations outside of the immune system and suggest new avenues for therapeutic development.
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