Gene regulation in the liver during iron overload

Despite its great significance for physiology, excess iron is detrimental. Iron overload disorders pose a major health concern. One such is Hemochromatosis which is associated by iron homeostasis dysregulation expressed by cellular deposits of excess iron. The liver plays a role in maintaining normal iron levels and preventing its toxicity by secreting a peptide named Hepcidin which is known to be heavily regulated. The scope of transcriptional regulation of iron homeostasis and its importance in physiology are largely unknown. Moreover, chromatin regulation of iron homeostasis, which is the backbone for transcriptional regulation is unexplored. Therefore, an understanding of iron homeostasis regulation has a therapeutic potential and may be beneficial for iron overload or anemia-related pathologies treatments.

Our Main goal is to characterize gene expression patterns and chromatin alteration during hepatic iron overload. C57BL/6 male mice were fed either chow diet as control or high iron diet (HID) of 2% carbonyl iron for 48h (acute treatment) or for 2 weeks (chronic treatment) in order to induce iron overload. By using RNA-seq we found that both chronic and acute HID cause major alterations in gene expression patterns. Moreover, major alterations in the liver chromatin structure were observed using ATAC-seq, with a remarkable effect on cell cycle-related genes. Genes from all cell cycle phases were induced. Motif enrichment analysis and BaGFoot analysis revealed an enrichment of cell cycle-related transcription factor motifs within the accessible chromatin. In Conclusion, High iron diet profoundly changes the transcriptional program and chromatin landscape of the liver.