title: Correlated 5-Hydroxymethylcytosine (5hmC) and Gene Expression Profiles Underpin Gene and Organ-Specific Epigenetic Regulation in Adult Mouse Brain and Liver.
abstract: BACKGROUND
  DNA methylation is an epigenetic mechanism essential for gene regulation and vital for mammalian development. 5-hydroxymethylcytosine (5hmC) is the first oxidative product of the TET-mediated 5-methylcytosine (5mC) demethylation pathway. Aside from being a key intermediate in cytosine demethylation, 5hmC may have potential regulatory functions with emerging importance in mammalian biology.
  
  
  METHODS
  Here, we investigate the global 5hmC enrichment in five brain structures, including cerebellum, cerebral cortex, hippocampus, hypothalamus and thalamus, as well as liver tissues from female and male adult mice by using chemical capture-based technique coupled with next-generation sequencing. At the same time, we carried out total RNA sequencing (RNA-seq) to analyze the transcriptomes of brain regions and liver tissues.
  
  
  RESULTS
  Our results reveal preferential 5hmC enrichment in the gene bodies of expressed genes, and 5hmC levels of many protein-coding genes are positively correlated with RNA expression intensity. However, more than 75% of genes with low or no 5hmC enrichment are genes encode for mitochondrial proteins and ribosomal proteins despite being actively transcribed, implying different transcriptional regulation mechanisms of these housekeeping genes. Brain regions developed from the same embryonic structures have more similar 5hmC profiles. Also, the genic 5hmC enrichment pattern is highly tissue-specific, and 5hmC marks genes involving in tissue-specific biological processes. Sex chromosomes are mostly depleted of 5hmC, and the X inactive specific transcript (Xist) gene located on the X chromosome is the only gene to show sex-specific 5hmC enrichment.
  
  
  CONCLUSIONS
  This is the first report of the whole-genome 5hmC methylome of five major brain structures and liver tissues in mice of both sexes. This study offers a comprehensive resource for future work of mammalian cytosine methylation dynamics. Our findings offer additional evidence that suggests 5hmC is an active epigenetic mark stably maintained after the global reprogramming event during early embryonic development.
authors.affiliation: VYM Genome Research Center, National Yang-Ming University, Taipei, Taiwan.|The Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: I-Hsuan
authors.initials: IH
authors.lastname: Lin
authors.affiliation: VYM Genome Research Center, National Yang-Ming University, Taipei, Taiwan.|The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.|Chien-Tien Hsu Cancer Research Foundation, Taipei, Taiwan.
authors.forename: Ming-Ta
authors.initials: MT
authors.lastname: Hsu
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000375:Aging / Q000235:genetics*; D000818:Animals; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism; D019175:DNA Methylation; D004622:Embryo, Mammalian; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020043:Genes, Essential; D016678:Genome; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism; D007031:Hypothalamus / Q000254:growth & development / Q000378:metabolism; D008099:Liver / Q000254:growth & development / Q000378:metabolism; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D012730:Sex Chromosomes / Q000737:chemistry / Q000378:metabolism; D013788:Thalamus / Q000254:growth & development / Q000378:metabolism; D059467:Transcriptome
chemical_list: D024101:Mitochondrial Proteins; D012269:Ribosomal Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine