Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory disease and a leading cause of progressive neurological disability among young adults. DNA methylation, which intersects genes and environment to control cellular functions on a molecular level, may provide insights into MS pathogenesis. METHODS: We measured DNA methylation in CD4+ T cells (n = 31), CD8+ T cells (n = 28), CD14+ monocytes (n = 35) and CD19+ B cells (n = 27) from relapsing-remitting (RRMS), secondary progressive (SPMS) patients and healthy controls (HC) using Infinium HumanMethylation450 arrays. Monocyte (n = 25) and whole blood (n = 275) cohorts were used for validations. FINDINGS: B cells from MS patients displayed most significant differentially methylated positions (DMPs), followed by monocytes, while only few DMPs were detected in T cells. We implemented a non-parametric combination framework (omicsNPC) to increase discovery power by combining evidence from all four cell types. Identified shared DMPs co-localized at MS risk loci and clustered into distinct groups. Functional exploration of changes discriminating RRMS and SPMS from HC implicated lymphocyte signaling, T cell activation and migration. SPMS-specific changes, on the other hand, implicated myeloid cell functions and metabolism. Interestingly, neuronal and neurodegenerative genes and pathways were also specifically enriched in the SPMS cluster. INTERPRETATION: We utilized a statistical framework (omicsNPC) that combines multiple layers of evidence to identify DNA methylation changes that provide new insights into MS pathogenesis in general, and disease progression, in particular. FUND: This work was supported by the Swedish Research Council, Stockholm County Council, AstraZeneca, European Research Council, Karolinska Institutet and Margaretha af Ugglas Foundation.

Epigenetic dysregulation of host gene expression in Toxoplasma infection with specific reference to dopamine and amyloid pathways.

Recent interest has focussed on the influence of infectious disease organisms on the host epigenome. Toxoplasma gondii infection acquired congenitally or in early life is associated with severe ocular and brain developmental anomalies, while persistent asymptomatic infection is a proposed risk factor for neurodegenerative and psychiatric disorders, including Parkinson's and Alzheimer's Diseases, and schizophrenia. Genome-wide analysis of the host methylome and transcriptome following T. gondii infection in a retinal cell line identified genes (132, 186 and 128 genes at 2, 6 and 24 h post-infection) concordant for methylation and expression, i.e. hypermethylated and decreased expression or hypomethylated and increased expression. Pathway analyses showed perturbation of two neurologically-associated pathways: dopamine-DARPP32 feedback in cAMP signalling (p-value = 8.3 × 10-5; adjusted p-value = 0.020); and amyloid processing (p-value = 1.0 × 10-3; adjusted p-value = 0.043). Amyloid Precursor Protein (APP) decreased in level following T. gondii infection. These results are of interest given the expression of APP early in nervous system development affecting neural migration and the role of amyloid processing in Alzheimer's disease, while dopamine has roles in the developing retina as well as in Parkinson's disease and schizophrenia. Our results provide a possible functional link between T. gondii infection and congenital/early life and adult neurological clinical signs.