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Published on: June 16, 2017
Whole-Genome DNA Methylation Analysis of Peripheral Blood Mononuclear Cells in Multiple Sclerosis Patients with
O G Kulakova1, M R Kabilov2, L V Danilova3
1Pirogov Russian National Research Medical University, Ostrovityanova str. 1, Moscow, 117997, Russia ; Institute of Experimental Cardiology, Russian Cardiology Scientific and Production Center, 3th Cherepkovskaya str. 15A, Moscow, 121552, Russia.
Abstract:
Multiple sclerosis (MS) is a severe neurodegenerative disease of polygenic etiology affecting the central nervous system. In addition to genetic factors, epigenetic mechanisms, primarily DNA methylation, which regulate gene expression, play an important role in MS development and progression. In this study, we have performed the first whole-genome DNA methylation profiling of peripheral blood mononuclear cells in relapsing-remitting MS (RRMS) and primary-progressive MS (PPMS) patients and compared them to those of healthy individuals in order to identify the differentially methylated CpG-sites (DMSs) associated with these common clinical disease courses. In addition, we have performed a pairwise comparison of DNA methylation profiles in RRMS and PPMS patients. All three pairwise comparisons showed significant differences in methylation profiles. Hierarchical clustering of the identified DMS methylation levels and principal component analysis for data visualization demonstrated a clearly defined aggregation of DNA samples of the compared groups into separate clusters. Compared with the control, more DMSs were identified in PPMS patients than in RRMS patients (67 and 30, respectively). More than half of DMSs are located in genes, exceeding the expected number for random distribution of DMSs between probes. RRMS patients mostly have hypomethylated DMSs, while in PPMS patients DMSs are mostly hypermethylated. CpG-islands and CpG-shores contain 60% of DMSs, identified by pairwise comparison of RRMS and control groups, and 79% of those identified by pairwise comparison of PPMS and control groups. Pairwise comparison of patients with two clinical MS courses revealed 51 DMSs, 82% of which are hypermethylated in PPMS. Overall, it was demonstrated that there are more changes in the DNA methylation profiles in PPMS than in RRMS. The data confirm the role of DNA methylation in MS development. We have shown, for the first time, that DNA methylation as an epigenetic mechanism is involved in the formation of two distinct clinical courses of MS: namely, RRMS and PPMS.
Insights
Epigenetic DNA methylation significantly differs between multiple sclerosis (MS) clinical courses. Primary-progressive MS shows more DNA methylation changes than relapsing-remitting MS, highlighting its role in disease progression.
Area of Science:
- Neuroscience
- Genetics
- Epigenetics
Background:
- Multiple sclerosis (MS) is a severe neurodegenerative disease with polygenic causes.
- Epigenetic mechanisms, particularly DNA methylation, are crucial in regulating gene expression and influence MS development.
- Understanding DNA methylation differences in distinct MS clinical courses is vital.
Purpose of the Study:
- To conduct the first whole-genome DNA methylation profiling in peripheral blood mononuclear cells of relapsing-remitting MS (RRMS) and primary-progressive MS (PPMS) patients.
- To identify differentially methylated CpG-sites (DMSs) associated with RRMS and PPMS compared to healthy individuals.
- To compare DNA methylation profiles between RRMS and PPMS patients.
Main Methods:
- Whole-genome DNA methylation profiling of peripheral blood mononuclear cells.
- Identification and analysis of differentially methylated CpG-sites (DMSs).
- Hierarchical clustering and principal component analysis for data visualization and group aggregation.
Main Results:
- Significant differences in DNA methylation profiles were observed between all compared groups (RRMS vs. control, PPMS vs. control, RRMS vs. PPMS).
- PPMS patients exhibited more DMSs (67) than RRMS patients (30) compared to controls.
- RRMS DMSs were predominantly hypomethylated, while PPMS DMSs were mostly hypermethylated, with a significant proportion located in genes and CpG-islands/shores.
Conclusions:
- DNA methylation plays a confirmed role in the development and progression of MS.
- Distinct DNA methylation patterns characterize the two major clinical courses of MS: RRMS and PPMS.
- Epigenetic mechanisms, specifically DNA methylation, are involved in the distinct formation of RRMS and PPMS phenotypes.
