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Oligodendroglia lineage cells, which form myelin sheats around neuronal axons, are crucial for neuronal communication and normal brain function. Impairment in these cells has been observed during aging and in various neurological disorders, yet the molecular mechanisms behind these changes remain largely unknown. Gaining insight into these processes is key for promoting healthy aging and developing effective therapies.
In the Functional Neurogenomics Lab, we tackle this important question from a novel perspective, by studying transposable elements (TEs). Despite being strong gene regulators and comprising more than half of our genome, TEs have been largely overlooked, leaving much to discover. Our previous work shows that TEs strongly influence gene expression in the human brain, often through interaction with their epigenetic repressors such as DNA methylation. This is particularly relevant because DNA methylation patterns are changing with age and disease, and play a key role in the differentiation, maturation and function of oligodendroglia linage cells. This represents our main research question: How do changes in epigenetic repression alter the impact of transposons in oligodendroglia and affect brain function?
Our research is driven by the hypothesis that alterations in DNA methylation over TEs lead to TE-derived gene expression changes and functional consequences in oligodendroglia. We aim to uncover the basic epigenetic processes that regulate TEs in this cell type and to study how age- and disease-related changes in this epigenetic repression drive TE mediated molecular and functional alterations.
Approach
Using human-derived material, including post-mortem tissue and advanced cell models, we combine cellular reprogramming with CRISPR-based gene and epigenome editing. Our multi-omics approach integrates long-read and single-cell DNA and RNA sequencing data with epigenome techniques with the help of TE tailored bioinformatic approaches.
Basic mechanisms
While our work and that of others has shown that TEs are strong gene regulators in the human brain, studies have primarily focused on neuronal cell types. Thus, despite its importance, our understanding about the gene regulatory influence of TEs in the oligodendroglia lineage is very limited. Therefore, we aim to uncover the diverse mechanisms by which TEs contribute to transcriptome complexity in oligodendroglia and the basic epigenetic mechanisms that regulate them. Understanding how TEs and their epigenetic repressors interact to regulate gene expression in this cell type under normal conditions will help reveal how these processes change when epigenetic repression is altered e.g. during aging and disease.
Healthy aging
Aging is associated with changes in DNA methylation and gene expression in oligodendroglia, but the underlying mechanisms and functional consequences remain unclear. Our lab is investigating the possibility that age-related DNA methylation changes over transposons drive TE-derived transcriptomic alterations and functional changes in aging oligodendroglia. As aging is the primary risk factor for neurodegenerative disorders, understanding how alterations in the epigenetic repression of TEs during healthy aging affect this cell type may reveal mechanisms that contribute to age-related brain disorders mediated by TEs.
Disease
While several age-related neurological disorders are characterized by molecular and functional alterations in oligodendroglia, the contribution of TEs to these processes remains poorly understood. To fill this gap, we study how disease-related DNA methylation changes over TEs affect oligodendrocyte function, focusing on X-Linked Dystonia-Parkinsonism (XDP), an adult-onset neurodegenerative disorder caused by a TE insertion. By characterizing the oligodendrocyte-specific regulatory and functional effects of the XDP-TE, we aim to guide the development of TE-targeted therapies and inform studies of TEs in other myelinating disorders like MS, ALS and MSA.
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