Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two fatal neurodegenerative diseases. A rare form of familial ALS is caused by mutations in the FUS gene that disrupt the nuclear localization sequence leading to cytoplasmic accumulation and aggregation of FUS. Besides genetic cases, FUS is also a component of protein inclusions in a subset of sporadic FTD cases (FTLD-FUS). Thus, cytoplasmic aggregation of the physiologically nuclear FUS protein is a typical feature of a subset of FTD and ALS collectively termed FUS-opathies. Neuropathology strongly suggests that neurodegeneration is directly related to cellular redistribution of FUS. The critical pathogenic event could be either reduced ability of FUS to perform its normal nuclear functions, a toxic gain of function of FUS in the cytoplasm, or a combination of both. FUS is a multifunctional DNA/RNA binding protein with described role as transcription regulator, as it interacts with transcription factors, proteins involved in the transcriptional machinery, as well as proteins involved in splice regulation. FUS can also indirectly modify transcription as it binds epigenetic regulators. Hence, in FUS-opathies, FUS mislocation could induce the cellular redistribution of one, or several, of these crucial proteins, thereby altering the homeostasis of histone modifications and ultimately, gene expression. While a link between chromatin modifications and FUS is suggested by recent in vitro studies, the complexity of chromatin structure modifications potentially regulated by FUS, as well as their downstream effects in the CNS and their pathomechanistic relevance for the disease, have never been studied. Thus, the goal of this project is to elucidate the link between FUS, its mutations and epigenetic modifications of the chromatin in vivo, and to correlate these data with subsequent transcriptomic alterations and phenotypes in transgenic FUS mice and FUS-opathies. We hypothesize that the redistribution of FUS modifies chromatin remodeling dynamics as well as associated epigenomic signatures which could in turn alter genetic programs relevant to cognitive functions and/or neurological deficits. To achieve this we gathered applicants that complement each other ideally by providing all necessary scientific expertise and technical know-how. The analysis of a unique collection of transgenic FUS mouse models with genome-wide and cell type-specific analysis of chromatin alterations (ChIPseq) and transcriptomic (RNAseq including splice variants) changes using next-generation sequencing approaches will allow a detailed dissection of the role of nuclear, cytoplasmic and mutated FUS in regulating chromatin composition and downstream effects as well as its pathogenetic relevance. Identifying a disease specific epigenetic signature would offer a direct path towards therapeutic intervention since various brain permeable small molecular regulators of chromatin remodeling enzymes are available.