The binding-site map was compiled with a novel two-step procedure called ChIP-on-chip. Researchers first used a technique called chromatin immunoprecipitation (ChIP) to purify the regions of genes that take orders from the ER. They then placed these pieces of DNA on "microarray chips" containing the entire human genome sequence. This allowed the researchers to identify all the points in the genome where binding with the ER takes place.
The researchers coined the word "cistrome" to describe the map they had produced -- an atlas of all gene segments influenced by the ER. "cis" refers to a DNA segment that regulates a gene's activity in response to a signal from outside the gene (while "trans" refers to a factor that acts on DNA); and "ome" -- from the Greek word for manager -- refers to the full set of such segments, as "genome" refers to all the genes within human cells.
The map contains many surprises, the study authors say. For one, the majority of binding sites within the cistrome are often very far from the portions of the genes that contain the blueprints for proteins. This overturns the commonly held notion that the ER might favor sites close to the protein-coding regions of genes.
"More than 70 percent of breast cancers are ER-positive, meaning their growth is driven by estrogen," Brown says, "and the estrogen receptor is the most important target for therapy for these tumors. Knowing the complete set of ER binding sites gives us a new resource for understanding the role of estrogen in breast cancer. By identifying genes associated with the ER in breast tumors, it opens up previously unexplored regions of the genome involved in the estrogen-dependence of breast cancer."
The knowledge may one day help researchers and physicians determine which treatments are likely to work best in individual patients and restore the potency of cancer drugs to which patients have become resistant, added Brown, who is also a profess
Source:Dana-Farber Cancer Institute