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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.

Dark Matter

Riley Hoonan

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.

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What Is Genetic Dark Matter?

Researchers are only beginning to understand genetic dark matter's many mysteries.

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1. “Genome Regulation by Long Noncoding RNAs,” by John L. Rinn and Howard Y. Chang, Annual Review of Biochemistry, July 2012. The authors, who have made major contributions to the understanding of long noncoding RNAs, review technologies enabling these studies and highlight emerging themes.

2. “The Evolution of Lineage-Specific Regulatory Activities in the Human Embryonic Limb,” by James P. Noonan et al., Cell, July 3, 2013. Noonan describes enhancers associated with the embryonic development of the distinctive human hand and foot.

3. “Xist RNA Is a Potent Suppressor of Hematologic Cancer in Mice,” by Jeannie T. Lee et al., Cell, Feb. 14, 2013. Some breast cancers have extra copies of the X chromosome, suggesting that these cancers may have malfunctioning Xist, a long noncoding RNA responsible for silencing the second X chromosome in females. Here, Lee and colleagues investigate whether Xist dysregulation might cause cancer, using blood cancer in mice as a test case.

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