Open Access Open Badges Research

Ontogeny, distribution and potential roles of 5-hydroxymethylcytosine in human liver function

Maxim Ivanov1*, Mart Kals2, Marina Kacevska1, Isabel Barragan1, Kie Kasuga3, Anders Rane4, Andres Metspalu256, Lili Milani26 and Magnus Ingelman-Sundberg1

Author Affiliations

1 Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, 17177 Stockholm, Sweden

2 Estonian Genome Center, University of Tartu, Riia 23b, 51010 Tartu, Estonia

3 Cancer Proteomics Mass Spectrometry, Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet Science Park, Tomtebodavägen 23A, 17165 Solna, Sweden

4 Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital at Huddinge, Medicingatan 5, 14186 Stockholm, Sweden

5 Estonian Biocentre, Riia 23b, 51010 Tartu, Estonia

6 AQ2 Institute of Molecular and Cell Biology, University of Tartu, Riia 23b, 51010 Tartu, Estonia

For all author emails, please log on.

Genome Biology 2013, 14:R83  doi:10.1186/gb-2013-14-8-r83

Published: 19 August 2013



Interindividual differences in liver functions such as protein synthesis, lipid and carbohydrate metabolism and drug metabolism are influenced by epigenetic factors. The role of the epigenetic machinery in such processes has, however, been barely investigated. 5-hydroxymethylcytosine (5hmC) is a recently re-discovered epigenetic DNA modification that plays an important role in the control of gene expression.


In this study, we investigate 5hmC occurrence and genomic distribution in 8 fetal and 7 adult human liver samples in relation to ontogeny and function. LC-MS analysis shows that in the adult liver samples 5hmC comprises up to 1% of the total cytosine content, whereas in all fetal livers it is below 0.125%. Immunohistostaining of liver sections with a polyclonal anti-5hmC antibody shows that 5hmC is detected in most of the hepatocytes. Genome-wide mapping of the distribution of 5hmC in human liver samples by next-generation sequencing shows significant differences between fetal and adult livers. In adult livers, 5hmC occupancy is overrepresented in genes involved in active catabolic and metabolic processes, whereas 5hmC elements which are found in genes exclusively in fetal livers and disappear in the adult state, are more specific to pathways for differentiation and development.


Our findings suggest that 5-hydroxymethylcytosine plays an important role in the development and function of the human liver and might be an important determinant for development of liver diseases as well as of the interindividual differences in drug metabolism and toxicity.