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Biological Chemistry and the Epigenetics Center
on what's missing in a two-dimensional view of a gene
Why have you and other scientists only recently begun to consider how a gene’s position in three-dimensional space might affect its activity?
REDDY: It is not an entirely new scientific question. It’s really an old idea. Scientists have known since before Watson and Crick that chromatin—the material composed of DNA and its companion proteins—is not just a random scramble of spaghetti. When scientists began looking at nuclei through electron microscopes, they saw two different types of chromatin: the darker and denser heterochromatin, and the lighter euchromatin. Later, they learned that euchromatin contains most of the active genes, while little gene activity took place within the heterochromatin.
But then we spent many decades focused on the molecular stuff, including gene sequencing. Now we’re starting to think more about how the spatial positioning of genes impacts molecular mechanisms. So we’re coming full circle.
Your “real estate hypothesis” says that the nuclear membrane plays an important role in activating or silencing genes. Do you think that all genes are regulated in this way?
REDDY: No, I don’t think so. But the number regulated in this manner has the potential to be quite large. Research suggests that close to 30 percent of genes are in contact with the nuclear membrane. We’d like to learn which genes those are.
There may be other compartments in the nucleus that serve as hiding places for genes, where genes don’t get transcribed, and others, including something called a splicing speckle, that might serve as a transcription factory. Some scientists are also studying an event called chromosome kissing, which may be involved in gene regulation. Parts of the same or different chromosome make contact, or “kiss,” in a way that may activate or repress genes.
How might the nuclear location of genes influence other events in the cell?
REDDY: I’ll give you one example. A chromosomal translocation occurs when a piece of a chromosome breaks off from one chromosome and attaches to another. Such translocations can occur in some forms of cancer. It is possible that the translocation causes a change in addressing. In other words, the chromosome might go to a place in the nucleus where it’s not supposed to go. Such incorrect routing could cause aberrations in gene expression that might lead to cancer. So this is basic biology, but it has huge implications.