Our Dark Matter
One way the three layers interact involves the relationships between two noncoding elements, promoters and enhancers, and the genes they influence. “The more we learn about regulatory elements, the more we realize the categories we have for them are more fluid than we thought,” says James Noonan, a geneticist at Yale University. Nevertheless, it’s generally understood that a promoter acts like a light switch that is activated by molecules called transcription factors to turn on a gene. Enhancers act as dimmer dials; they recruit transcription factors and guide them to a targeted promoter, and that interaction modulates gene expression. However, enhancers often lie at an immense distance from the promoters they target. They come together thanks to the looping of DNA strands, but exactly how that works remains a mystery.
Each enhancer may bind many transcription factors, and each gene may be regulated by many enhancers—and every cell type has different sets of transcription factors and enhancers. “Enhancers are highly specific for certain tissues, cell types, time points in development, and environmental conditions or external stimuli,” says Axel Visel, a staff scientist in the genomics division at Lawrence Berkeley National Laboratory in Berkeley, Calif.
Visel notes that enhancers, because they have been conserved through the evolution of species, are thought to have played a fundamental role in those gradual genetic changes. “Nature held on to these elements because they do something important,” says Visel, who is currently studying evolutionarily conserved enhancers that affect the formation of the face, brain, heart and other organ systems. Meanwhile, though, some enhancers were changed, and others were occasionally added in separating humans from their ancestral species. Yale’s Noonan thinks such “human gain” enhancers may control some of people’s most distinguishing features: hands and feet, dexterous fingers, upright posture, face, cranium and brain. “To understand what makes humans distinct from other species, we need to understand how human development is different,” says Noonan.
In his work, Noonan focused first on limb development because it was comparatively well understood and because it’s an area in which humans evolved quite differently than other species. In a study published in Cell in July 2013, he and his colleagues compared embryonic tissue in humans, rhesus monkeys and mice during four developmental stages. He found several thousand enhancers that were more active in humans, including many that were associated with genes involved in the formation and shapes of tendons, cartilage, the big toe and height. Now he’s testing whether the human versions of these enhancers will affect development in mouse models. Next he plans to apply this method to the development of the brain.