Figure 8.

Proposed schematic of HDAC5-mediated H3K9ac and H3K27ac regulation of gene expression and affected biological pathways in WD. In WD, copper overload and oxidative stress might lead to phosphorylation of AMPK (active form). Increased phosphorylated AMPK could then phosphorylate HDAC5, which is subsequently exported to the cytosol. Lack of nuclear HDAC5 and increased histone acetyltransferase (HAT1) might cause an increase in acetylated histones (H3K9ac and H3K27ac) and decrease methylated histones (H3K9me3 and H3K27me3) with subsequent altered regulation of genes in WD. Our results show HDAC5 impacts the acetylation/methylation balance and serves as a critical regulator of genes central in metabolic regulation. ChIP-seq and RNA-seq revealed 3732 differentially expressed genes in the tx-j mouse model of WD, and the enrichment analysis of these genes included pathways related to lysine degradation, fatty acid metabolism, carbon metabolism, pyruvate metabolism, and signal transduction. PI3K-AKT, phosphatidylinositol-3-kinase and protein kinase B.