Are found in genes exclusively PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26240184 in fetal livers and disappear in the adult state, are more specific to pathways for differentiation and development. Conclusions: 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.Background There are substantial interindividual differences in many liver processes, including intermediary metabolism, protein synthesis, carbohydrate metabolism and the detoxification of drugs and other xenobiotics. With respect to variation in drug metabolism, transport and toxicity, much knowledge has been gained from studies investigating genetic factors responsible for interindividual differences. However, little is known regarding the role of epigenetic factors, such as DNA modifications and their influence on hepatic gene expression, function and interindividual variation [1]. The epigenetic DNA modifications include methylation and hydroxymethylation of cytosine. For many* Correspondence: [email protected] Contributed equally 1 Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz v 2, 17177 Stockholm, Sweden Full list of author information is available at the end of the articleyears, 5-methylcytosine (5mC) was believed to be the only epigenetic modification of genomic DNA, often referred to as `the fifth base’ of the genome. Recently, 5hydroxymethylcytosine (5hmC) was discovered as a novel epigenetic factor in mammalian DNA that can have a stable effect on gene transcription and has hence been regarded as `the sixth base’ of the genome [2,3]. 5hmC originates from an enzymatic oxidation of 5mC by TET1, TET2 and TET3 proteins [2,4], which recognize their substrate 5mC by the amino-terminal CXXC zinc (-)-Blebbistatin site finger domain [5]. This reaction is dependent on Fe 2+ as well as a-ketoglutarate; the latter, in turn, is dependent on the activity of either isocitrate dehydrogenase IDH1 in the cytosol and peroxisomes or IDH2 and IDH3 in mitochondria [6,7]. Although other proteins may also have some significance in establishing the presence of genomic 5hmC, the TET and IDH proteins seem to play a very important role as determinants of the global 5hmC content.?2013 Ivanov et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Ivanov et al. Genome Biology 2013, 14:R83 http://genomebiology.com/2013/14/8/RPage 2 ofHydroxymethylcytosine can serve as an intermediate of active DNA demethylation if further oxidized by TET enzymes to 5-formylcytosine (5fC) and then to 5-carboxylcytosine (5caC), which in turn is removed by thymine-DNA glycosylase. The resulting abasic site is repaired by the base excision repair mechanism, producing unmethylated cytosine [8,9]. The level of 5fC was found to be extremely low in mouse embryonic stem cells and brain cortex (0.02 to 0.002 from total cytosine) [9,10]. Despite the recent progress in genome-wide mapping of 5fC in mouse embryonic stem cells, there is still no convincing evidence for its role as an epigenetic modification [11,12]. In contrast, 5hmC is 10 to 100 times more abundant.
