title: Ontogeny, distribution and potential roles of 5-hydroxymethylcytosine in human liver function.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  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.
authors: Maxim
authors: M
authors: Ivanov
authors: Mart
authors: M
authors: Kals
authors: Marina
authors: M
authors: Kacevska
authors: Isabel
authors: I
authors: Barragan
authors: Kie
authors: K
authors: Kasuga
authors: Anders
authors: A
authors: Rane
authors: Andres
authors: A
authors: Metspalu
authors: Lili
authors: L
authors: Milani
authors: Magnus
authors: M
authors: Ingelman-Sundberg
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000328:Adult; D000367:Age Factors; D050260:Carbohydrate Metabolism / Q000235:genetics; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D015894:Genome, Human; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000254:growth & development / Q000378:metabolism*; D058977:Molecular Sequence Annotation; D014176:Protein Biosynthesis / Q000235:genetics
chemical_list: C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine
references: Bioinformatics. 2009 Jul 15;25(14):1754-60
references: 19451168
references: Mol Cell. 2011 May 20;42(4):451-64
references: 21514197
references: Cell. 2012 Jun 8;149(6):1368-80
references: 22608086
references: Clin Pharmacol Ther. 2012 Dec;92(6):727-36
references: 23093317
references: Nature. 2010 Aug 26;466(7310):1129-33
references: 20639862
references: Genome Res. 2012 Mar;22(3):467-77
references: 22106369
references: Nucleic Acids Res. 2011 Jul;39(12):5015-24
references: 21378125
references: Nat Biotechnol. 2010 May;28(5):495-501
references: 20436461
references: Angew Chem Int Ed Engl. 2011 Jul 11;50(29):6460-8
references: 21688365
references: Nature. 2011 May 19;473(7347):398-402
references: 21460836
references: Science. 2009 May 15;324(5929):929-30
references: 19372393
references: Nucleic Acids Res. 2010 Oct;38(19):e181
references: 20685817
references: Nature. 2011 May 19;473(7347):394-7
references: 21552279
references: Genome Biol. 2012 Aug 17;13(8):R69
references: 22902005
references: Genes Dev. 2011 Apr 1;25(7):679-84
references: 21460036
references: Cell Cycle. 2009 Jun 1;8(11):1698-710
references: 19411852
references: PLoS Genet. 2011 Jun;7(6):e1002154
references: 21731508
references: J Nucleic Acids. 2011;2011:870726
references: 21772996
references: Science. 2011 Sep 2;333(6047):1303-7
references: 21817016
references: Angew Chem Int Ed Engl. 2011 Jul 25;50(31):7008-12
references: 21721093
references: Nat Neurosci. 2011 Oct 30;14(12):1607-16
references: 22037496
references: Cell Res. 2011 Sep;21(9):1332-42
references: 21747414
references: Cell. 2012 Sep 14;150(6):1135-46
references: 22980977
references: Nucleic Acids Res. 2012 Sep 1;40(17):8255-65
references: 22730288
references: Cell. 2013 Apr 25;153(3):678-91
references: 23602153
references: Science. 2009 May 15;324(5929):930-5
references: 19372391
references: Nucleic Acids Res. 2004 Aug 09;32(14):4100-8
references: 15302911
references: Cell Rep. 2013 Feb 21;3(2):291-300
references: 23403289
references: J Natl Cancer Inst. 2010 Jul 7;102(13):932-41
references: 20513808
references: Oncotarget. 2011 Aug;2(8):627-37
references: 21896958
references: Nat Biotechnol. 2011 Jan;29(1):68-72
references: 21151123
references: Int J Cancer. 2012 Oct 1;131(7):1577-90
references: 22234893
references: Genome Biol. 2008;9(9):R137
references: 18798982
references: Cell. 2011 Dec 23;147(7):1498-510
references: 22196727
references: Cancer Cell. 2011 Jan 18;19(1):17-30
references: 21251613
references: Cell Stem Cell. 2011 Feb 4;8(2):200-13
references: 21295276
references: Bioinformatics. 2009 Aug 15;25(16):2078-9
references: 19505943
references: Genome Biol. 2011 Jun 20;12(6):R54
references: 21689397
references: PLoS One. 2010 Dec 23;5(12):e15367
references: 21203455
references: Science. 2011 Sep 2;333(6047):1300-3
references: 21778364
references: Nature. 2011 May 19;473(7347):343-8
references: 21490601
references: PLoS One. 2010 Jan 26;5(1):e8888
references: 20126651
references: Genome Biol. 2012 Oct 03;13(10):R93
references: 23034186
references: PLoS One. 2010 Sep 02;5(9):
references: 20824057