title: Regional activation of the cancer genome by long-range epigenetic remodeling.
abstract: Epigenetic gene deregulation in cancer commonly occurs through chromatin repression and promoter hypermethylation of tumor-associated genes. However, the mechanism underpinning epigenetic-based gene activation in carcinogenesis is still poorly understood. Here, we identify a mechanism of domain gene deregulation through coordinated long-range epigenetic activation (LREA) of regions that typically span 1 Mb and harbor key oncogenes, microRNAs, and cancer biomarker genes. Gene promoters within LREA domains are characterized by a gain of active chromatin marks and a loss of repressive marks. Notably, although promoter hypomethylation is uncommon, we show that extensive DNA hypermethylation of CpG islands or "CpG-island borders" is strongly related to cancer-specific gene activation or differential promoter usage. These findings have wide ramifications for cancer diagnosis, progression, and epigenetic-based gene therapies.
authors.affiliation: Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Saul A
authors.initials: SA
authors.lastname: Bert
authors.forename: Mark D
authors.initials: MD
authors.lastname: Robinson
authors.forename: Dario
authors.initials: D
authors.lastname: Strbenac
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Statham
authors.forename: Jenny Z
authors.initials: JZ
authors.lastname: Song
authors.forename: Toby
authors.initials: T
authors.lastname: Hulf
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Marcel W
authors.initials: MW
authors.lastname: Coolen
authors.forename: Clare
authors.initials: C
authors.lastname: Stirzaker
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Clark
mesh_terms: D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics*
chemical_list: D006657:Histones; D035683:MicroRNAs