Molecular mechanism for the multiple sclerosis risk variant rs17594362
| Autor: | Yungki Park, Dongkyeong Kim |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Linkage disequilibrium Multiple Sclerosis Population Single-nucleotide polymorphism Biology Polymorphism Single Nucleotide Linkage Disequilibrium 03 medical and health sciences 0302 clinical medicine Genetics medicine Demyelinating disease Humans Genetic Predisposition to Disease Allele Enhancer education Molecular Biology Genetics (clinical) Alleles Chromosome 13 education.field_of_study Chromosomes Human Pair 13 Multiple sclerosis General Medicine medicine.disease 3. Good health 030104 developmental biology Enhancer Elements Genetic General Article 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 |
| Popis: | Multiple sclerosis (MS) is known as an autoimmune demyelinating disease of the central nervous system. However, its cause remains elusive. Given previous studies suggesting that dysfunctional oligodendrocytes (OLs) may trigger MS, we tested whether single nucleotide polymorphisms (SNPs) associated with MS affect OL enhancers, potentially increasing MS risk by dysregulating gene expression of OL lineage cells. We found that two closely spaced OL enhancers, which are 3 Kb apart on chromosome 13, overlap two MS SNPs in linkage disequilibrium—rs17594362 and rs12429256. Our data revealed that the two MS SNPs significantly up-regulate the associated OL enhancers, which we have named as Rgcc-E1 and Rgcc-E2. Analysis of Hi-C data and epigenome editing experiments shows that Rgcc is the primary target of Rgcc-E1 and Rgcc-E2. Collectively, these data indicate that the molecular mechanism of rs17594362 and rs12429256 is to induce Rgcc overexpression by potentiating the enhancer activity of Rgcc-E1 and Rgcc-E2. Importantly, the dosage of the rs17594362/rs12429256 risk allele is positively correlated with the expression level of Rgcc in the human population, confirming our molecular mechanism. Our study also suggests that Rgcc overexpression in OL lineage cells may be a key cellular mechanism of rs17594362 and rs12429256 for MS. |
| Databáze: | OpenAIRE |
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