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Our Dark Matter

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Accumulating research suggests that the role of the noncoding genome might be even more important than protein-coding genes in understanding how human diseases develop. For example, in February 2013, two groups independently identified the same two closely related mutations in a promoter that regulates telomerase, an enzyme that almost all cancers exploit so that they can divide indefinitely. More than 70% of melanoma tumors had this promoter mutation. That kickstarted a series of additional studies that have found the same two promoter mutations in many cancers—in 44% of hepatocellular carcinomas, 66% of bladder cancers and 83% of glioblastomas. In all cases, those mutations are more prevalent than any gene mutation that has been identified.

Enhancers are also being linked to disorders in which mutations in protein-coding genes have proven hard to find. For example, a genome-wide association study found a sequence that significantly increases the risk of being born with a cleft of the lip or palate. “But there was not a single protein-coding gene in that sequence,” says Visel. In a 2013 Science study, however, he reported that he found in this region at least two enhancers that are implicated in facial development and may act on genes that sit outside the region. It may be that the gene itself isn’t mutated in the disease but rather that the problem lies with an enhancer that regulates the gene.

Similarly, Lee of MGH has linked the lncRNA Xist to blood cancer in mice. Could those cancers have defective X inactivation? In a February 2013 article in Cell, she described deleting Xist in embryonic blood stem cells in mice, causing all of the blood cells in the developing female mice to have two active X chromosomes. The upshot? All of the female mice missing Xist developed blood cancers. But none of the male mice without Xist had problems—because, having only one X chromosome, they don’t need X inactivation. “If we could reintroduce Xist or use some other technique to inactivate the second X chromosome, it might suppress these cancers,” Lee says.

Meanwhile, researchers at University of Massachusetts Medical School recently exploited Xist’s capacity to silence an entire chromosome for a study of Down syndrome, in which children are born with an extra copy of chromosome 21. Working with cells in culture, the researchers inserted Xist and saw it create the “cloud” that silences the X chromosome, and the same condensed form that kept its genes shut down.

It remains to be seen how Rinn’s bet on the importance of lncRNAs will play out. So far, he and others have studied only a relative handful of what could be thousands of these noncoding RNAs, and scientists are also only beginning to explore other regulatory elements. Even if most of the known elements have a significant impact on human biology, together they account for but a tiny part of the genome. Still, the importance of known noncoding regulatory elements may rival that of the 1.5% of the genome that contains protein-coding genes.

What’s important for now is that many noncoding elements merit exploring in animal models of human diseases. The results of those tests, many hope, will provide clearer glimpses into our vast genome and bring us closer to the secrets we had hoped to discover when we began translating the human “book of life” in 2000. So far those glimpses inspire the same sense of wonder as the Fermi Gamma-ray Space Telescope that was sent out to explore what the Fermilab calls the “numerous exotic and beautiful phenomena” in the dark matter of the material universe.

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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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