CoEN: Investigating chromatin landscapes in neurodegenerative disease models

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Neurodegenerative diseases (NDs) are highly debilitating conditions that represent a major economic burden for the developed world. While progress has been made in controlling symptoms pharmacologically, virtually no therapeutic options exist for the treatment of these conditions. This is due to the small number of known ND-causing genetic changes and their limited use as therapeutic targets. It is therefore critical to investigate how additional, nongenetic molecular alterations can drive ND initiation and progression. In this respect, alteration of the way the DNA is packed in the nucleus (chromatin) and its consequences on gene expression have been suggested to contribute to ND pathogenesis. However, our understanding of NDassociated chromatin modifications is mostly based on analysis of human post-mortem tissues or on in vitro preclinical models that do not recapitulate the complexity of NDs. The present application aims to provide an in-depth analysis of chromatin changes over the course of ND pathogenesis using faithful in vivo preclinical models and to correlate these changes back to ND hallmark pathological features. Overall, this study will provide key insights into the dynamic nature of ND-associated chromatin alterations and will constitute the basis for further work aimed at identifying new targets for therapeutic intervention.