Gene regulation study reports surprising results: Wide region of DNA belongs to multiple gene switches
Certain sequences in the genome cause genes to be turned on or off. Until now, each of these gene switches, or so-called enhancers, was thought to have its own place in the DNA. Different enhancers are therefore isolated from each other, even if they control the same gene and turn it on in different parts of the body.
A recent study from the University of Bonn and LMU Munich challenges this idea. The results are also important because gene switches are thought to play a central role in evolution. The study is published in the journal Science Advances.
The blueprint for the form of plants and animals is encoded in their DNA. But only a small part of the genome—about two percent in mammals—contains genes, the instructions for making proteins. The rest essentially controls when and where these genes are active: how many copies of them are made and thus how many proteins are made from these copies.
Some of these regulatory sequences, called “enhancers,” work like the dimmer switches we use to modulate the lighting in our living rooms. In effect, they specifically increase the expression of a particular gene, where and when that gene is needed. Genes that control morphology often respond to several independent enhancers, each determining gene expression in a different part of the body.
Drosophila color-controlling enhancers
Until now, enhancers were thought to be modular. The term implies that each enhancer occupies a discrete stretch of DNA.
"But we have shown that this is not entirely true," explains Mariam Musseridze. She is a Ph.D. student at the Bonn Institute of Organismic Biology in the team of Professor Dr. Nicholas Gompel and the first author of the study. Gompel is a member of the Transdisciplinary Research Area (TRA) "Life and Health" at the University of Bonn.
The researchers studied how a gene called turmeric is regulated in the fruit fly Drosophila. This gene makes the insect produce brown melanin. There are many enhancers that control the activity of turmeric. One of them, for example, is responsible for the pigmentation of maggots' teeth, while another is responsible for the formation of striped patterns on the fly's abdomen.
"We took a closer look at these two enhancers," says Musseridze.
The first controls the formation of the color pattern on the wings, the second controls the color of the head, thorax and abdomen. Both are active at the same time during the fly's metamorphosis. The team discovered that the body enhancer is not located in a different region of DNA from the wing enhancer, as expected.
Instead, there are broad regions of DNA that belong to both gene switches, meaning they affect pigmentation of both wings and the body.
The results suggest that the architecture of regulatory sequences in the genome is much more complex than previously thought. This has far-reaching implications for how traits change during evolution. According to current knowledge, enhancers play a key role in this process.
This is because many proteins are so important for an organism that a mutation in their genes (that is, the DNA sequence that contains the instructions for making a protein) can cause serious problems or even certain death. As a result, genes that control body shape, such as the number of wings or legs, have changed very little during evolution. Enhancers offer a way out of this dilemma: when they mutate, the activity of the corresponding gene changes, but only in a specific tissue and at a specific time.
