Sox2 function as a negative regulator to control HAMP expression.

Bin Song,An-An Liu,Rui Liu,Ying-Qi Zhou,Cheng-Hao Shao,Qi Bian,Gang Li,Gang Jin,Wei Jing,Yi-Jie Zhang

doi:10.1186/s40659-015-0013-z

Bin Song, An-An Liu + Show 8 more

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https://doi.org/10.1186/s40659-015-0013-z

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Abstract

BackgroundHepcidin, encoding by HAMP gene, is the pivotal regulator of iron metabolism, controlling the systemic absorption and transportation of irons from intracellular stores. Abnormal levels of HAMP expression alter plasma iron parameters and lead to iron metabolism disorders. Therefore, it is an important goal to understand the mechanisms controlling HAMP gene expression.ResultsOverexpression of Sox2 decrease basal expression of HAMP or induced by IL-6 or BMP-2, whereas, knockdown of Sox2 can increase HAMP expression, furthermore, two potential Sox2-binding sites were identified within the human HAMP promoter. Indeed, luciferase experiments demonstrated that deletion of any Sox2-binding site impaired the negative regulation of Sox2 on HAMP promoter transcriptional activity in basal conditions. ChIP experiments showed that Sox2 could directly bind to these sites. Finally, we verified the role of Sox2 to negatively regulate HAMP expression in human primary hepatocytes.ConclusionWe found that Sox2 as a novel factor to bind with HAMP promoter to negatively regulate HAMP expression, which may be further implicated as a therapeutic option for the amelioration of HAMP-overexpression-related diseases, including iron deficiency anemia.Electronic supplementary materialThe online version of this article (doi:10.1186/s40659-015-0013-z) contains supplementary material, which is available to authorized users.

Highlights

Hepcidin, encoding by HAMP gene, is the pivotal regulator of iron metabolism, controlling the systemic absorption and transportation of irons from intracellular stores
Overexpression of Sox2 decrease HAMP expression in hepatoma-derived cells We searched HAMP expression with BioGPS database and the analysis suggest that HAMP is highly and expressed in liver tissue (Additional file 1: Figure S1)
Anemia of chronic disease is a condition caused by increased HAMP production, and is a result of inflammation [7,8]

Summary

Introduction

Hepcidin, encoding by HAMP gene, is the pivotal regulator of iron metabolism, controlling the systemic absorption and transportation of irons from intracellular stores. Abnormal levels of HAMP expression alter plasma iron parameters and lead to iron metabolism disorders. The expression of the HAMP is increased in patients with anemia of chronic disease. It has become clear that inflammatory cytokines released during acute infection or chronic disease can alter systemic iron metabolism by inducing excess synthesis of hepcidin [4,7,8,10]. Due to the central role of HAMP as described above, inhibition of its biological activity or its expression level may be promising new approaches for the treatment of anemia associated disease

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