"We thought that Ezh2 might serve as a direct link from receptor signaling to nuclear responses," says Tarakhovsky. "But proof for Ezh2 as a methyltransferase, which we learned that it is, simply did not exist prior to our studies." Su, Tarkahovsky and their colleagues studied how Ezh2 does its job in the B cell. What they found, by using a special kind of knockout mouse, and a novel mass spectroscopy analysis is that Ezh2 controls methylation of histone H3 on one particular lysine residue, or biochemical modification site, on what is known as the histone "tail."
Conditional, not conventional
Immunologists were among the vanguard of molecular biologists to tinker with the genes of the mouse. Early on, naturally occurring mutant mouse strains indicated the ability to probe the immune system by artificially deleting or adding a gene. Unfortunately, many genes that could be "knocked in" or "knocked out" are critical for the embryonic or early postnatal development. Creating a conventional knock out animal, in which a gene is eliminated from the beginning, would not allow the analysis of the immune system because embryological development could not progress without the gene.
Between 1989 and 1994, when genetically altered mice gained popularity as a powerful new research tool, immunologists developed another kind of genetic alteration system in mice in order to solve the problem of how to study a gene by knocking it out when it also plays a role in development. In 1994, a Cologne-based group headed by Klaus Rajewsky generated the first tissue-specific knockout mouse.