Oral Presentation 6th Australian Health and Medical Research Congress 2012

Regional Activation of the Cancer Genome by Long Range Epigenetic Remodelling  (#246)

Susan J Clark 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

Epigenetic deregulation is involved in cancer initiation and progression, but most studies have concentrated on gene repression and hypermethylation of tumour suppressor genes. Therefore the mechanism underpinning epigenetic-based gene activation in carcinogenesis is still poorly understood.  Previously, we reported that epigenetic changes could occur over large domains, resulting in concordant gene repression by Long Range Epigenetic Silencing (LRES).  Here, we identify a contrasting mechanism of domain gene regulation, through coordinate Long Range Epigenetic Activation (LREA) of multiple adjacent genes.  By an integrative epigenome-wide analysis of prostate cancer and normal cells, we found 35 LREA regions, typically spanning 1Mb, harbouring key oncogenes, miRNAs, gene fusions and prostate cancer biomarker genes; PCA3 (prostate cancer antigen 3) and PSA (prostate specific antigen).  In contrast to LRES regions, gene promoters within LREA domains are characterised by a gain of active (H3K9ac and H3K4me3) chromatin marks, as well as loss of repressive (H3K9me2 and H3K27me3) marks.  Notably, whilst promoter hypomethylation did not commonly contribute to gene activation, extensive DNA hypermethylation of CpG islands or “CpG island borders” was strongly related to either cancer-specific gene activation or a change in promoter usage.  We show for the first time that LREA is a significant event in tumourigenesis, and is associated with the ectopic activation of domains that harbour critical tumour related genes. These findings have wide ramifications for cancer diagnosis, progression and epigenetic-based gene therapies.