Lisa Stubbs: Exploring What Makes Us Different
Exploring Learning, Behavior and Synaptic Plasticity
Lisa Stubbs, who joined the University of Illinois in March 2008, adds a key new dimension to IGB: an expertise in mouse genetics.
"You can do things with mice that you can't do with other model species," says Stubbs. "I'm hoping that my colleagues and I can go after problems together and that my mouse expertise will really help. Our transcription factors work puts us squarely into the field of epigenetics, which is something both Gene (Robinson) and David (Clayton) are very interested in, in terms of learning, behavior and synaptic plasticity."
Although Stubbs started her scientific career investigating and identifying genetic similarities between mice and humans, it has been the differences between the two model systems that have, ultimately, captured her imagination.
"About 95 percent of genes are the same between humans and mice, including most genes that encode transcription factors," says Stubbs. "And so, we can typically extrapolate what we learn from gene expression regulation in the mouse directly over to humans. For quite a few years we focused precisely on this high degree of similarity, and it is still valid for most genes. However, when we looked closer, we found one large class of transcription factor genes that are really different between species."
It is these differences that came to intrigue Stubbs.
"It turns out that when we look closely at the genome sequence, yes there are lots of similarities [between mice and humans], but there are some really interesting differences, too," she says. "The similarities are such a dominant theme that when you see these things that are really different it kind of blows your mind. Because these genes that are not shared are very likely to be defining why we're biologically different."
Stubbs has focused on the genes that encode transcription factors known as Krüppel-type zinc-finger proteins. This transcription factor family is the only one that varies widely between different animals.
"Every species has its own set of these transcription factors," says Stubbs. "Insects, birds, mice and humans, each has its own. Even though we have mostly very similar genomes, when the shared genes are regulated differently you can get very different outcomes."
In mammals, the rapidly changing zinc-finger genes belong to a specific subclass called the KRAB-ZNF genes; there are about 400 genes of this type in the human genome. Given that each transcription factor can control the expression of 100 or more "target genes," this is a big and complex story. That is, no surprise, a big part of the challenge.
The proteins Stubbs is studying have been shown to interact with the cell's chromatin modification machinery, "shutting down" certain regulatory elements so they cannot bind other proteins. This is one way that gene expression can be changed, not by changing the DNA sequence per se, but changing the state of the chromatin around it, and therefore, its epigenetic state. Those changes can be both experience dependent and biology dependent, and through binding of proteins like the KRAB-ZNFs, very specific to only certain genes. This theory postulates a mechanism through which gene expression can evolve more nimbly, from species to species, but also in response to the environment, than previously imagined.
One particularly compelling aspect of the KRAB-ZNF genes for Stubbs and her IGB colleagues is that they have found that many primate-specific transcription factors appear to be focused on neuronal development. The KRAB-ZNFs themselves and the genes they regulate tend to be expressed in the nervous system.
"There is a large subclass of these transcription factors, especially primate-specific ones, that are active in the brain," says Stubbs. "They may be controlling certain pathways of neural development involved in behavior and other aspects of brain function that are very different between species, such as learning capacity."