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How do scientists turn genes on and off in living animals?

Miriam Meisler, a professor of human genetics at the University of Michigan at Ann Arbor, explains.

Francois Jacob and Jacque Monod, working out of an attic laboratory in Paris, first explored the mechanisms for turning genes on and off 50 years ago. They studied gene regulation in bacteria and discovered that sugars in the food supply turn on the genes required for their own digestion. In addition, when bacteria are transferred from a medium containing the sugar lactose to a medium without lactose, the bacteria turn off their lactose-metabolizing genes. The mechanism for this switch is based on a regulatory protein called the lac repressor, which binds to a short, 23-base-pair DNA sequence located on the bacterial chromosome adjacent to the lactose digestion genes. This efficient method coordinates gene expression with physiological requirements.

In the 1970s and 1980s, scientists discovered that gene regulation in mammals also uses the mechanism of protein recognition of short DNA sequences. These short regulatory sequences are called enhancers. For example, the hormone testosterone binds a receptor protein that recognizes a 15-base-pair DNA sequence. As a result, genes that contain this sequence can be activated by testosterone. Estrogen, in contrast, regulates a different set of genes that have their own distinct sequence. Researchers can exploit enhancers in experiments by fusing a known enhancer to a gene that they want to regulate. As an example, one might fuse the estrogen enhancer to the hemoglobin gene and insert the construct into the chromosome of a so-called transgenic mouse. When the resulting transgenic mouse is treated with estrogen, the hemoglobin gene will be turned on.

In addition to hormones, there are other chemicals that can be used to regulate gene expression. In one currently popular type of experiment, the antibiotic tetracycline is used to activate a gene called CRE in specific cell types, resulting in rearrangement of the chromosomal DNA. Another current application involves shutting off cancer-causing genes after a tumor has developed. If the tumor regresses when the cancer gene is turned off, then it follows that regulation of that gene could be a way to treat that tumor type.

Turning genes on and off is a major activity of all living cells. Almost 10 percent of the genes in the human genome produce proteins that regulate the expression of other genes. Some regulatory proteins control embryonic development, like the PAX2 protein, which activates specific genes during eye development. Other regulators respond to changing environmental signals, such as the amount of protein or trace metals in the diet. Scientists are using the knowledge about gene regulation plus new cloning tools to investigate the physiological effects of switching specific genes on or off in living animals.

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