Unveiling the functional outcome of single nucleotide polymorphisms and variants in oligodendroglia in multiple sclerosis

Introduction

Multiple sclerosis (MS) is a neurological disease characterized by autoimmune attack targeting oligodendroglia (OLG) in the central nervous system (CNS), and in particular their myelin, which ensheaths neuronal axons. Genome-wide association studies (GWAS) have led to the identification of hundreds of single-nucleotide polymorphisms (SNPs) and variants that are associated with MS risk.

Role of Immune Cells

Many of these SNPs/variants are located near genes associated with immune cells, indicating a key role for these cells in MS. Using single-cell omics approaches, we recently found that OLG present chromatin accessibility or express genes associated with some of these SNPs/variants, both in health and disease.

Hypothesis and Objectives

Here, we hypothesize that OLG have a more active role in MS than previously anticipated. Therefore, we will determine the function of MS SNPs/variants in OLG in the context of MS, using humanized mouse models, patient samples, and new single-cell omics techniques recently developed in my group.

Specific Aims

We will:

1. Characterize in-depth the transcriptomic and epigenomic landscape of human and mouse OLG in the context of MS, to identify putative genes affected by the SNPs/variants.
2. Perform CRISPR-guided editing of a cohort of the identified SNPs/variants in human OLG, and determine the consequences of the editing at: a) An epigenomic and transcriptional level, linking specific SNPs/variants to their bona-fide target genes. b) A functional level, by performing an array of functional assays targeting myelination, cell survival, and immune function, both in vitro and in humanized mouse chimeras in which engineered human OLG have been transplanted.

Methodology

We will use single-cell and spatial omics technologies, such as nanoCUT&Tag and spatial CUT&Tag, among others which we have recently developed in my research group.

Expected Outcomes

The results of this project will yield unique insights into the role of OLG and the identified SNPs/variants in MS, and thereby pave the way to novel therapeutic avenues for this disease.