Mutant FUS induces chromatin reorganization in the hippocampus and alters memory processes

This project aims to assess the transcriptomic signature of FUS∆NLS/+ (FUS) vs FUS+/+ (WT) mice, by identifying differentially expressed genes in basal conditions and also during learning. Cytoplasmic mislocalization of the nuclear Fused in Sarcoma (FUS) protein is associated to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS accumulation is recapitulated in the frontal cortex and spinal cord of heterozygous Fus∆NLS/+ mice. We show that in these mice, the hippocampus, a critical structure involved in learning and memory, paradoxically displays nuclear FUS accumulation. FUS binds to a set of genes characterized by the presence of an ETS/ELK-binding motifs, and involved in RNA metabolism, transcription, ribosome/mitochondria and chromatin organization. Importantly, hippocampal nuclei showed a decompaction of the neuronal chromatin at highly expressed genes and an inappropriate transcriptomic response was observed after spatial training of Fus∆NLS/+ mice. Furthermore, these mice lacked precision in hippocampal-dependent spatial memory task. These studies shows that mutated FUS affects epigenetic regulation of the chromatin landscape in hippocampal neurons, which could participate in FTD/ALS pathogenic events. Total RNAs were extracted from the dorsal hippocampus (HD) of 4-5 month-old FUS+/+ (WT) and FUS∆NLS/+ (FUS) mice at basal state (Home Cage, HC) and after 3 days of training in the Morris Water Maze (MWM). In total, we have 4 groups : WT and FUS mice Home Cage, and WT and FUS mice after learning. Each group includes 3 samples for sequencing with a total of 12 samples for dorsal hippocampus. Data were generated by deep sequencing using Illumina Hiseq 4000.