Dynamic chromatin accessibility during nutritional iron overload reveals a BMP6-independent induction of cell cycle genes

Talia Radushkevitz-Frishman, Meital Charni-Natan, Ido Goldstein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Iron is essential to organism physiology as it participates in numerous biological processes including oxygen transport, respiration, and erythropoiesis. Although iron is critical to physiology, excess iron is toxic to cells and tissues due to generation of reactive oxygen species. Therefore, well-kept iron homeostasis is a mainstay of proper cell and organ function. Iron overload disorders, caused by nutritional or genetic factors, contribute to many pathologies such as diabetes, non-alcoholic steatohepatitis and hepatocellular carcinoma. The liver is not only vulnerable to the effects of iron overload, it is also the major organ controlling iron homeostasis. During iron overload, Bone Morphogenic Protein (BMP) levels increase and initiate a hepatic response aimed at lowering iron levels. The transcriptional effects of iron overload are not well-characterized and the underlining enhancer regulation is uncharted. Here, we profiled the liver's transcriptome and chromatin accessibility following nutritional iron overload. We found marked changes in gene expression and enhancer accessibility following iron overload. Surprisingly, 16% of genes induced following iron overload participate in propagating the cell cycle. Induction of cell cycle genes was independent of BMP. Genome-wide enhancer landscape profiling revealed hundreds of enhancers with altered activity following iron overload. Characterization of transcription factor motifs and footprints in iron-regulated enhancers showed a role for the Activator Protein 1 (AP-1) transcription factor in promoting cell cycle-related transcription. In summary, we found that the transcriptional program at play during iron overload is bifurcated in which BMP signaling controls iron homeostasis genes while an AP-1-driven program controls cell cycle genes.

Original languageAmerican English
Article number109407
JournalJournal of Nutritional Biochemistry
Volume119
DOIs
StatePublished - Sep 2023

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Inc.

Keywords

  • AP-1
  • Cell cycle
  • Chromatin
  • Enhancers
  • Iron
  • Transcriptional regulation

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