DNA methylation of hepatic iron sensing genes and the regulation of hepcidin expression

Production of the iron regulatory peptide hepcidin is tightly controlled by a network of proteins in hepatocytes that sense levels of iron in the circulation (as diferric-transferrin) and in tissues (in ferritin). Human studies show high variability in the normal range of serum hepcidin levels. We h...

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Bibliographic Details
Published in:PloS one 2018-05, Vol.13 (5), p.e0197863-e0197863
Main Authors: Sharp, Paul A, Clarkson, Rachel, Hussain, Ahmed, Weeks, Robert J, Morison, Ian M
Format: Article
Language:English
Subjects:
Biology and life sciences
Biotechnology
Cancer
Cell lines
Cellular proteins
Demethylation
Deoxyribonucleic acid
Detection
DNA
DNA methylation
Epigenetics
Ferritin
Gene expression
Gene regulation
Gene silencing
Genes
Hepatocytes
Hepatoma
Hepcidin
Homeostasis
Human performance
Iron
Iron and steel making
Liver
Liver cancer
Medicine and Health Sciences
Methylation
Primers
Prostate
Proteins
Research and Analysis Methods
Rodents
Transcription
Transferrin
Transferrins
Variability
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Summary:Production of the iron regulatory peptide hepcidin is tightly controlled by a network of proteins in hepatocytes that sense levels of iron in the circulation (as diferric-transferrin) and in tissues (in ferritin). Human studies show high variability in the normal range of serum hepcidin levels. We have postulated that this may, in part, be related to inter-individual variability in the expression of genes in the iron sensing pathway, potentially governed by epigenetic factors. Here, we have investigated whether genes encoding hepatic iron sensing proteins and hepcidin are regulated by DNA methylation. Experiments were performed on two human hepatoma cell lines, HepG2 cells and Huh7 cells. Basal expression of TFR2 and HAMP was significantly lower in Huh7 cells compared with HepG2 cells. Analysis of bisulphite-converted DNA from Huh7 cells revealed partial methylation of TFR2 (alpha transcript), which could result in gene silencing. Demethylation using 5-aza-2'-deoxycitidine (AZA) increased TFR2 mRNA expression in Huh7. PCR analysis of bisulphite-converted HAMP promoter DNA, using methylation-specific primers, revealed no differences between cell lines. However, HAMP mRNA expression in Huh7 was increased by AZA treatment, suggesting that methylation of one or more iron sensing genes may indirectly influence HAMP expression. Our study provides evidence that DNA methylation might control expression of HAMP and other hepatic iron sensing genes, and indicates that epigenetic influences on iron homeostasis warrant further investigation.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0197863