While much has been written about The Human Genome Project over the years, the full story may just now be unfolding. Literally.
Inside each normal, nucleated cell, a lot of DNA is tightly packed. Uncoiled, it would stretch almost nine feet. Magnified 1,000 times to better see it, the length would be three kilometers – the equivalent distance of the Lincoln Memorial to the capital of Washington, D.C.
In a paper published today in the journal Nature, Bing Ren, PhD, head of the Laboratory of Gene Regulation at the Ludwig Institute for Cancer Research at UC San Diego, and colleagues describe for the first time how different parts of DNA are actually folded next to each other inside a cell’s nucleus.
Question: Why is it important to know where genes are positioned within the nucleus?
Answer: One thing that we know is there are between 20 and 30 thousand genes in the human genome, but in any one cell, only a subset of them are turned on. We know that one important factor in deciding which of the genes in the genome are turned on in any one cell is where they are positioned in the nucleus, and where they are positioned relative to other parts of the genome. For example, we know that there are certain regions of the genome that are called enhancers, and these act like switches that turn on genes. The trick is that the enhancer that is responsible for turning on a gene may not be located right next to the gene, and in fact may be some distance away, almost like a light switch that turns on the lights in another room.
So we know that at least one of the ways that these enhancers work is that they are brought in close physical proximity to the gene they regulate by bending the DNA and causing a large loop to form in the genome. This “looping” allows the enhancer to work in turning on its target gene. So it is this kind of physical association of different parts of the genome that can play a critical role in deciding which genes a cell turns on, which is what we were hoping to learn something about in our study.
Q: You call these identified regions “topological domains.” What do they look like? Does their structure explain how they work?
A: With regards to what the topological domains look like, we can’t say for certain, but it is something that we are interested in. What we know from what we have found is that the topological domains are regions of the genome that are tightly self-associated. It’s as if these domains are parts of our genome that are wound up like a ball of yarn, and that our genome is composed of many of these domains, over and over again, but that each of the domains appears to be relatively separate from each of the neighboring domains, like many balls of yarn linked together.
Q: What’s the significance of your finding that these domains are highly conserved and appear ancient in origin?
A: We think the finding that these domains are conserved in evolution is really interesting. In the case of humans and mice, these are organisms that are believed to be separated by 65 million years of evolution, yet we can see that in the parts of the human and mouse genomes that are analogous to each other, the structures can be remarkably similar.
In addition, there was another group that showed recently that the genome of fruit flies, which are even further away on the evolutionary tree, are arranged with a similar topological domain structure. Exactly what all this means isn’t entirely clear, but it suggests that this strategy of organizing genomes into topological domains was something that was hit on very early in animal evolution, and appears to be something that has been retained quite strongly. This suggests that this is an effective way for animals to organize their genomes. Perhaps by segregating our genome into these domains, it is easier to regulate the function of different regions of the genome. We are hoping that as we learn more about how these domains function, this may allow us to make better predictions about why they have been retained so well in evolution, and this may tell us something about how we and other organisms have evolved our genomes.
Q: How are these findings likely to be used by other researchers?
A: We hope our paper will be a good resource for other scientists studying genome function. For example, what we have done is to essentially create large-scale maps of how the genome is folding up in embryonic stem cells and differentiated cells. As I mentioned earlier, we know that the way that certain genes may be turned on are via these long range “loopings” between enhancers and distant genes.
We hope these maps of how the genome is folding up and interacting may give researchers clues about which regions of the genome may regulate which genes, and this is important for understanding how any particular gene is normally regulated, and how that regulation may be altered in disease.