Wilson disease: intersecting DNA methylation and histone acetylation regulation of gene expression in a mouse model of hepatic copper accumulation

Abstract

The pathogenesis of Wilson disease (WD) is multi-factorial, involving hepatic and brain copper accumulation due to pathogenic variants affecting the ATP7B gene and downstream epigenetic and metabolic mechanisms. Prior DNA methylation investigations in human WD liver and blood and in a WD mouse model revealed an epigenetic signature of WD, including alterations in the histone deacetylase HDAC5. To test the hypothesis that histone acetylation is altered with respect to copper overload and aberrant DNA methylation in WD, we investigated class IIa histone deacetylases (HDAC4 and HDAC5) and H3K9/H3K27 histone acetylation in the Jackson Laboratory toxic milk (tx-j) mouse model of WD compared to C3HeB/FeJ (C3H) control in response to 3 treatments: 60% kcal fat diet (HFD), D-penicillamine (PCA, copper chelator), and choline (methyl group donor). HDAC5 levels significantly increased in 9-week tx-j livers after 8 days of HFD compared to chow. In 24-week tx-j livers, HDAC4/5 levels were reduced 5- to 10-fold compared to C3H likely through mechanisms involving HDAC phosphorylation. HDAC4/5 levels were also affected by disease progression and accompanied by increased acetylation. PCA and choline partially restored HDAC4, HDAC5, H3K9ac, and H3K27ac levels to that of CH3 liver. Integrated RNA and chromatin immunoprecipitation sequencing analyses revealed genes regulating energy metabolism and cellular stress/development were, in turn, regulated by histone acetylation in tx-j mice compared to C3H, with Pparα and Pparγ among the most relevant targets. These results suggest dietary modulation of class IIa HDAC4/5, and subsequent H3K9/H3K27 acetylation/deacetylation, can regulate gene expression in key metabolic pathways in the pathogenesis of WD.