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Good fences make good neighbors — Stanford researchers unravel mystery about a well-known cancer culprit

Stanford researchers solve a long-standing mystery as to how mutations in a neighboring stretch of DNA can increase the expression of a cancer-associated gene called Myc. The finding highlights a potential new class of targets to block cancer cell growth.

On the Montana farm where I grew up, the "good fences make good neighbors" saying goes without saying. No one wants a surprise visit from the cattle, horses or hogs next door, which can wreak havoc on a crop of hay or a well-tended lawn.

Turns out appropriately maintained boundaries are just important in our genomes as on our properties. Genome scientist Howard Chang, MD, PhD, and postdoctoral scholars Seung Cho, PhD, and Jin Xu, PhD, have found that a section of DNA separating a well-known cancer-associated gene called Myc from another called Pvt1 performs a vital role in tamping down the Myc's cancer-causing activity.

They published their findings in Cell.

As Chang explained to me:

Over the last couple years, we've begun to discover that DNA in cells is folded in a fairly organized manner that puts genes and their control elements into the proper locations. Scientists have also been finding that defects in these boundary elements can lead to birth defects and cancers. But we didn't know exactly how these boundary elements work. Now we know it's a much more dynamic situation than we had previously thought.

Pvt1 belongs to a class of genes called long non-coding RNAs, or lncRNAs. As the name suggests, these genes are used to make RNA molecules, but, unlike conventional RNA messages, lncRNAs are not used to make proteins. Instead they perform critical regulatory functions in the cell. In the case of Pvt1, researchers have known for many years that mutations in or around the gene can cause cancer, but it wasn't clear why.

As Chang explained:

Only two percent of the genome is made up of genes that encode instructions for proteins, but for decades most cancer research has focused on gene mutations that change the function or expression levels of proteins. We wanted to know how these non-coding RNAs affect cancer risk.

The expression of many genes is governed by interactions between regions called promoters near the start of the coding regions and other, more distant elements called enhancers that further amp up gene expression when they are brought into contact with the promoter. (Check out this fun, animated video from Chang's lab about how researchers are beginning to suss out the three-dimensional structures of RNA molecules.)

Chang, Cho and Xu found that the promoter region of Pvt1, which acts as a kind of genetic fence between Myc and Pvt1, interacts with enhancer elements within the Pvt1 gene. When the promoter region is mutated, however, these enhancers find a new partner in the Myc promoter and increase its levels of expression. This finding has important clinical implications for human cancers.

As Chang explained:

Myc expression is elevated in many types of human cancers. Now we're finding that enhancers in the neighboring gene are the culprits. When the boundary element is compromised, the Pvt1 enhancers can reach over to turn on Myc instead. So this is an interesting new class of target.

Photo by Phil Roeder

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