Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band.
We report a new mechanism in carcinogenesis involving coordinate long-range epigenetic gene silencing. Epigenetic silencing in cancer has always been envisaged as a local event silencing discrete genes. However, in this study of silencing in colorectal cancer, we found common repression of the entire 4-Mb band of chromosome 2q.14.2, associated with global methylation of histone H3 Lys9. DNA hypermethylation within the repressed genomic neighborhood was localized to three separate enriched CpG island 'suburbs', with the largest hypermethylated suburb spanning 1 Mb. These data change our understanding of epigenetic gene silencing in cancer cells: namely, epigenetic silencing can span large regions of the chromosome, and both DNA-methylated and neighboring unmethylated genes can be coordinately suppressed by global changes in histone modification. We propose that loss of gene expression can occur through long-range epigenetic silencing, with similar implications as loss of heterozygosity in cancer.
Frigola
Jordi
J
Cancer Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney 2010, New South Wales, Australia.
Song
Jenny
J
Stirzaker
Clare
C
Hinshelwood
Rebecca A
RA
Peinado
Miguel A
MA
Clark
Susan J
SJ
D002843:Chromatin / Q000235:genetics; D002871:Chromosome Banding; D002889:Chromosomes, Human, Pair 2; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002843:Chromatin