title: Dynamic interplay between locus-specific DNA methylation and hydroxymethylation regulates distinct biological pathways in prostate carcinogenesis.
abstract: BACKGROUND
  Despite the significant global loss of DNA hydroxymethylation marks in prostate cancer tissues, the locus-specific role of hydroxymethylation in prostate tumorigenesis is unknown. We characterized hydroxymethylation and methylation marks by performing whole-genome next-generation sequencing in representative normal and prostate cancer-derived cell lines in order to determine functional pathways and key genes regulated by these epigenomic modifications in cancer.
  
  
  RESULTS
  Our cell line model shows disruption of hydroxymethylation distribution in cancer, with global loss and highly specific gain in promoter and CpG island regions. Significantly, we observed locus-specific retention of hydroxymethylation marks in specific intronic and intergenic regions which may play a novel role in the regulation of gene expression in critical functional pathways, such as BARD1 signaling and steroid hormone receptor signaling in cancer. We confirm a modest correlation of hydroxymethylation with expression in intragenic regions in prostate cancer, while identifying an original role for intergenic hydroxymethylation in differentially expressed regulatory pathways in cancer. We also demonstrate a successful strategy for the identification and validation of key candidate genes from differentially regulated biological pathways in prostate cancer.
  
  
  CONCLUSIONS
  Our results indicate a distinct function for aberrant hydroxymethylation within each genomic feature in cancer, suggesting a specific and complex role for the deregulation of hydroxymethylation in tumorigenesis, similar to methylation. Subsequently, our characterization of key cellular pathways exhibiting dynamic enrichment patterns for methylation and hydroxymethylation marks may allow us to identify differentially epigenetically modified target genes implicated in prostate cancer tumorigenesis.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON Canada ; Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto, ON Canada.
authors.forename: Shivani N
authors.initials: SN
authors.lastname: Kamdar
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON Canada.
authors.forename: Linh T
authors.initials: LT
authors.lastname: Ho
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON Canada.
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Kron
authors.affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: Isserlin
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON Canada ; Department of Pathology, University Health Network, University of Toronto, Toronto, ON Canada.
authors.forename: Theodorus
authors.initials: T
authors.lastname: van der Kwast
authors.affiliation: Department of Surgery and Surgical Oncology, Division of Urology, University Health Network, University of Toronto, Toronto, ON Canada.
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Zlotta
authors.affiliation: Division of Urology, University Health Network, Toronto, ON Canada.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Fleshner
authors.affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON Canada.
authors.forename: Gary
authors.initials: G
authors.lastname: Bader
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON Canada ; Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto, ON Canada.
authors.forename: Bharati
authors.identifier: 0000-0002-7684-1338
authors.initials: B
authors.lastname: Bapat
mesh_terms: D063646:Carcinogenesis / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000209:etiology* / Q000235:genetics; D014407:Tumor Cells, Cultured
keywords: 5-Hydroxymethylcytosine; 5-Methylcytosine; Cell lines; Integrative analysis; Prostate cancer; Whole-genome