DNA methylation signatures of monozygotic twins clinically discordant for multiple sclerosis

Area of Science:

• Neuroimmunology
• Epigenetics
• Genomics

Background:

• Multiple sclerosis (MS) is a central nervous system inflammatory disease.
• Its modest concordance in identical twins suggests a role for epigenetic factors.
• Understanding these factors is crucial for MS research.

Purpose of the Study:

• To investigate epigenetic differences, specifically DNA methylation, in monozygotic twins discordant for MS.
• To identify potential epigenetic biomarkers associated with MS and its treatments.
• To establish a reference for future epigenomic studies in MS.

Main Methods:

• Analysis of methylomes in peripheral blood mononuclear cells from 45 MS-discordant monozygotic twin pairs.
• Identification and validation of differentially methylated positions (DMPs) and regions.
• Correlation analysis of methylation patterns with MS status and treatment history (interferon-beta, glucocorticoids).

Main Results:

• Highly similar methylomes were observed between co-twins, indicating a strong genetic influence.
• Seven MS-associated DMPs were identified, with two validated: a TMEM232 promoter region and a ZBTB16 enhancer.
• An MS-associated differentially methylated region in FIRRE was found in CD4+ T cells.
• Epigenetic signatures for interferon-beta and glucocorticoid treatments were identified, with ZBTB16 DMP linked to prior glucocorticoid use.

Conclusions:

• Epigenetic modifications, particularly DNA methylation, are relevant in the pathogenesis of MS.
• Specific DMPs, like ZBTB16, may serve as biomarkers for treatment history.
• Genetic background and treatment confounders must be considered in epigenomic MS research.