"By looking at the transgenic mice we noticed that their prostate and mammary glands were blue," Nobrega noted, "indicating the presence of regulatory sequences within the piece of human DNA that we were testing." They then focused on the prostate, identifying the specific enhancer driving the observed expression pattern.
The group could then engineer a version of the enhancer that contained a risk variant associated with prostate cancer and test this in mice. The prostate enhancer harboring the risk allele in the sequence drove expression of the reporter gene significantly higher in the mouse prostate relative to the normal version of the enhancer.
"The fact that a single nucleotide difference so markedly altered the enhancer's activity within the context of a living organism clearly demonstrates the potential impact that variation within non-coding gene regulatory elements could have on disease state," Nobrega noted.
Previous research has indicated that this enhancer modifies activity of a nearby gene called MYC, a proto-oncogene that exhibits altered expression in prostate cancers. However, those studies found no correlation between the risk allele enhancer and MYC expression in normal or cancerous prostate tissues, suggesting altered MYC expression may not be the biological factor conferring risk to disease in these cases.
The authors further explained that the risk variant enhancer activity was observed in the prostate throughout organogenesis and development, suggesting that the cancer risk variant might assert its influence very early, long before a tumor forms. "This strengthens the notion of a pathogenic process that could initiate much earlier in life than the appearance of clinical alterations, one in which thi
|Contact: Peggy Calicchia|
Cold Spring Harbor Laboratory