We study how transposable elements regulate gene expression in the healthy and diseased human brain across different biological contexts, with a focus on glial cells.
Human brain aging, whether healthy or pathological, is the main risk factor for the development of neurodegenerative disorders that affect millions worldwide. Gaining insight into this process is essential 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 altered with age and in neurodegenerative disorders, representing our main research question: How do age-related changes in epigenetic repression alter the impact of transposons in our brain?
Our research vision is driven by the hypothesis that during aging there are alterations in DNA methylation over TEs, leading to TE-derived gene expression changes and the development of neurodegenerative disorders. To study this, we focus on the white matter, known to be greatly affected during aging, and its main cell type, oligodendrocytes. Using patient-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 methods.
Overall, our research is driven by our curiosity about gene regulation in the human brain and aims to untangle the intricate dynamics between aging, transposable elements, and their epigenetic repressors. By developing TE-targeted epigenetic restoration strategies, we aim to bridge the gap between mechanistic understanding and therapeutic innovation.