Mutant FUS induces chromatin reorganization in the hippocampus and alters memory processes [H3K27me3 ChIP-seq]

This project aims to identify the H3K27me3 epigenomic signatures of FUS∆NLS/+ (FUS) vs FUS+/+ (WT) mice, using ChIP-sequencing performed on FACS-sorted nuclei. 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 hippocampus from 5 month-old FUS∆NSL/+ (FUS) and FUS+/+ (WT) mice were sorted by FACS to isolate neuronal nuclei that were then subjected to ChIP-sequencing using antibodies against the H3K27me3 histone mark. For this experiment, we have biological replicates (2 independent lots of mice). We will compare the epigenetic profiles of this mark in WT vs FUS mice in NeuN+ FACS-sorted nuclei. We have INPUT DNA For each of the 4 conditions (2 WT and 2 FUS). Overall, this represents 8 samples.