C017 Connecting metabolic and epigenetic dysregulations in Huntington’s disease

<h3></h3> Huntington’s disease (HD) is a genetic neurodegenerative disease that damages primarily the striatum and leads to motor, cognitive and psychiatric symptoms. The HD striatum undergoes epigenetic gene reprogramming, leading to impairment of striatal neuron identity and function. Notably, genes that define striatal neurons identity are progressively down-regulated due to decreased of histone acetylation (H3K27ac, H3K9ac). On the opposite, developmental genes show an increase in H3K27ac and H3K9ac, leading to their derepression. Energy metabolism is also early impaired in the HD striatum. Histone acetylation is strongly connected to energy metabolism through Acetyl-CoA (ACoA), the only donor of acetyl group for histone acetylation. Moreover, additional acyl-CoAs contribute to histone acylation, including lactyl-CoA, Crotonyl-CoA …, leading to histone lactylation, histone crotonylation, … thereby helping adjusting gene expression program to metabolic status. The aim of the project is to explore the hypothesis that deficient energy metabolism interplays with histone acylation changes in the HD striatum, impairing gene expression. Using HD mouse models, we further characterize HD striatal histone acylome, implementing ChIPseq/CUT&amp;Tag approach at cell-type-specific level. Our data indicate that H3K18ac and H3K12ac are depleted at genes associated with neuronal identity, contributing to their downregulation. Furthermore, our preliminary epigenetic and molecular analyses suggest that additional acylation marks (H3K18La, H3K9Cr, H3K18Cr) are modified in the HD striatum, indicating impairment of the histone acylome balance. Together, this supports the hypothesis of interplay between altered energy metabolism and histone acylome dysregulation in the HD striatum.