A045 Accelerated epigenetic aging involves polycomb group proteins in Huntington’s disease

<h3>Background/Aims</h3> With age, differentiated cells undergo a progressive erosion of epigenetic landscape and loss of cellular identity. Specifically, epigenetic aging involves H3K27ac depletion at cellular identity genes and their subsequent repression, together with H3K27me3-mediated derepression of developmental genes, normally silenced in differentiated cells. Yet, it is unclear whether such a mechanism occurs in brain cells, particularly in neurons, and whether it might contribute to neurodegenerative process, such that at play in Huntington’s disease (HD). In previous studies, we showed an early and progressive loss of H3K27ac at striatal identity genes, suggesting acceleration of epigenetic aging in HD vulnerable tissue. However, temporal dynamics and cell-type specificity of the mechanism was elusive. <h3>Methods</h3> We assessed the epigenomic landscape of neuronal and non-neuronal striatal cells of two reference HD mouse models (transgenic R6/1 and knock-in Q140), including temporal analysis at three ages corresponding to distinct pathological stages, using FANS-ChIPseq/FANS-CUT&amp;Tag and targeting H3K27me3 as well as histone acetylation marks. <h3>Results</h3> We show that the HD mutation accelerates, specifically in neurons, epigenetic repression of identity genes as well as derepression of developmental genes. Moreover, we uncover that derepression of developmental genes involves polycomb repressive complex 1 (PRC1). Temporal analysis also enlighten that the epigenetic regulation of anti-senescence genes is altered along HD progression. <h3>Conclusions</h3> Together, our data provide evidence for acceleration of epigenetic aging implicating PRC1 in HD vulnerable neurons, thereby opening new conceptual frame to foster translational studies.