Abstract
Systemic iron homeostasis involves a negative feedback circuit in which the expression level of the peptide hormone hepcidin depends on and controls the iron blood levels. Hepcidin expression is regulated by the BMP6/SMAD and IL6/STAT signaling cascades. Deregulation of either pathway causes iron-related diseases such as hemochromatosis or anemia of inflammation. We quantitatively analyzed how BMP6 and IL6 control hepcidin expression. Transcription factor (TF) phosphorylation and reporter gene expression were measured under co-stimulation conditions, and the promoter was perturbed by mutagenesis. Using mathematical modeling, we systematically analyzed potential mechanisms of cooperative and competitive promoter regulation by the transcription factors, and experimentally validated the model predictions. Our results reveal that hepcidin cross-regulation primarily occurs by combinatorial transcription factor binding to the promoter, whereas signaling crosstalk is insignificant. We find that the presence of two BMP-responsive elements enhances the steepness of the promoter response towards the iron-sensing BMP signaling axis, which promotes iron homeostasis in vivo. IL6 co-stimulation reduces the promoter sensitivity towards the BMP signal, because the SMAD and STAT transcription factors compete for recruiting RNA polymerase to the transcription start site. This may explain why inflammatory signals disturb iron homeostasis in anemia of inflammation. Taken together, our results reveal why the iron homeostasis circuit is sensitive to perturbations implicated in disease.
Highlights
Hepcidin is a humoral polypeptide that plays a central role in systemic iron homeostasis
The analysis showed that the presence of multiple redundant regulatory elements in the hepcidin gene promoter facilitates homeostasis, because changes in iron blood levels are sensed with high sensitivity
We further suggest that inflammatory signals establish molecular competition at the hepcidin promoter, thereby reducing its iron sensitivity and leading to a loss of homeostasis in anemia of inflammation
Summary
Hepcidin is a humoral polypeptide that plays a central role in systemic iron homeostasis (reviewed in [1]). One main function of hepcidin is to maintain constant levels of iron circulating in the blood despite imbalances in external iron availability: Iron overload in the blood stimulates hepcidin transcription in hepatocytes. Hepcidin in turn blocks intestinal iron uptake and macrophage iron release into the blood by binding to the iron exporter ferroportin and triggering its degradation. Hepcidin is part of a negative feedback circuit that stabilizes the iron blood concentration. Negative feedback is known to play a key role for the robustness and homeostasis of biochemical networks (reviewed in [2]). Biochemical negative feedbacks have been shown to compensate for various perturbations including stochasticity in gene expression [3,4], mutations [5] and pharmacological inhibition [6,7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
