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Gene Control
New gene-regulating enzyme found

Context: The Human Genome Project catalogued our genes, but all that genetic information is useless unless it’s tied to physical traits. One of the biggest remaining questions in biology is simply how genes are turned on and off. Part of the answer lies inside the cell’s nucleus, where DNA is wrapped around spool-like structures called histones. In the late 1990s, researchers found that enzymes placed chemical tags on the spools and that these tags could activate or deactivate genes on the wrapped DNA. What the researchers couldn’t find were enzymes that removed the tags, leading many to conclude that they just didn’t exist. A team at Harvard Medical School and Johns Hopkins School of Medicine led by Yang Shi has now found such an enzyme, and with it a new layer of gene control not previously exploited by medicine.

Methods and Results: Shi’s team was not originally looking for a detagging enzyme. Instead, it was investigating how the enzyme LSD1 (important for embryonic patterning and differentiation), as part of a larger protein complex, manages to suppress huge families of genes. After several experiments, the team realized that when LSD1 wasn’t around, certain genes were expressed because a histone that should not have been tagged in fact was. Closer observation of cells in which LSD1 was present revealed remnants of removed tags, confirming the enzyme’s behavior. It also showed that LSD1 clips tags at very specific spots, thereby exerting control over a discrete set of genes.

Why it Matters: Improperly tagged histones are implicated in several types of cancer. The discovery of this enzyme solves the second half of a mystery in gene regulation. Controlling this and related enzymes could lead to new therapies, particularly for cancers such as leukemia and neurodegenerative diseases. Further off, the enzyme could be used in bioengineered cells to turn large swaths of genes on and off without interfering with other techniques of gene regulation. Shi’s group has submitted a patent application on LSD1. Now, the search begins for more such enzymes.

Source: Shi, Y., et al. 2004. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119:941–953.

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Tagged: Biomedicine

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