Figure 4.

Correlation between iron status as reflected in serum ferritin concentration and expression levels of VHL^R200W induced genes, across 24 VHL^R200W homozygotes (8 iron sufficient plus 16 iron deficient individuals).

A. The density distribution of Spearman's ρ between expression level and serum ferritin concentration in VHL^R200W homozygotes for genes induced (red) or suppressed (black) at FDR 0.05 and genes exhibiting no difference at this FDR (grey) by the VHL^R200W mutation. The expression of a proportion of genes up-regulated by VHL^R200W homozygosity tended to have a negative correlation with serum ferritin concentration suggesting an up regulation by iron deficiency (enhanced by low iron), while an additional proportion of genes tended to have a positive correlation with serum ferritin , suggesting a down regulation by iron deficiency (suppressed by low iron).

B. The density distribution of Spearman's ρ between gene expression level and serum ferritin concentration for genes induced in VHL^R200W homozygotes that were not (black; n =2282) or that were (red, N = 100) HIF-2 targets. HIF-2 targets that were induced in VHL^R200W homozygotes tended to have a positive correlation with serum ferritin concentration, suggesting down regulation by iron deficiency. HIF-2 targets were detected at 10% FDR in VHL−/− and HIF1A−/− renal clear cell carcinoma cell lines with and without HIF2A knocked down, using published microarray data [33].