Gene expression patterns in the progression of canine copper-associated chronic hepatitis

<div><p>Copper is an essential trace element, but can become toxic when present in abundance. The severe effects of copper-metabolism imbalance are illustrated by the inherited disorders Wilson disease and Menkes disease. The Labrador retriever dog breed is a novel non-rodent model for copper-storage disorders carrying mutations in genes known to be involved in copper transport. Besides disease initiation and progression of copper accumulation, the molecular mechanisms and pathways involved in progression towards copper-associated chronic hepatitis still remain unclear. Using expression levels of targeted candidate genes as well as transcriptome micro-arrays in liver tissue of Labrador retrievers in different stages of copper-associated hepatitis, pathways involved in progression of the disease were studied. At the initial phase of increased hepatic copper levels, transcriptomic alterations in livers mainly revealed enrichment for cell adhesion, developmental, inflammatory, and cytoskeleton pathways. Upregulation of targeted <i>MT1A</i> and <i>COMMD1</i> mRNA shows the liver’s first response to rising intrahepatic copper concentrations. In livers with copper-associated hepatitis mainly an activation of inflammatory pathways is detected. Once the hepatitis is in the chronic stage, transcriptional differences are found in cell adhesion adaptations and cytoskeleton remodelling. In view of the high similarities in copper-associated hepatopathies between men and dog extrapolation of these dog data into human biomedicine seems feasible.</p></div

Additional file 3: of A high-resolution gene expression atlas of epistasis between gene-specific transcription factors exposes potential mechanisms for genetic interactions

Contribution of selection criteria to genetic interaction types. (A) Hierarchical clustering of GSTF pairs selected on growth-based genetic interaction scores, represented as in Fig. 3. Clustering was performed on the epistatic effects. GSTF pairs marked with a solid circle were also selected based on similarity in DNA binding. Colored branches depict example groups described in the text. (B) Hierarchical clustering of GSTF pairs selected based on similarity in DNA binding, represented as in A. GSTF pairs marked with a solid circle also exhibit a genetic interaction as derived by growth on agar plates [11]. (PDF 339 kb

Additional file 1: of A high-resolution gene expression atlas of epistasis between gene-specific transcription factors exposes potential mechanisms for genetic interactions

List of putative GSTFs and strains used. (XLSX 27 kb