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Biological Chemistry

Controlling gene expression with light

Method switches epigenetic enzyme on and off using light-controlled small-molecule inhibitors

by Michael Torrice
April 4, 2016 | APPEARED IN VOLUME 94, ISSUE 14

Chemical biologists have reported a method to control gene expression in cells with enzyme inhibitors triggered by visible light (Nat. Chem. Biol. 2016, DOI: 10.1038/nchembio.2042). The new tool could help scientists study how epigenetics regulate gene expression, as well as lead to possible therapeutics that can be pinpointed to specific bits of tissue. Epigenetic enzymes in cells can control gene expression by adding or removing chemical groups to and from histone proteins that serve as packing material for DNA. One of these chemical modifications involves acetylation of histone lysines. A team led by Ralph Mazitschek and Stephen J. Haggarty of Massachusetts General Hospital designed light-controlled inhibitors of enzymes called histone deacetylases (HDACs), which remove these acetyl groups. The control molecules are based on known HDAC inhibitors and feature an azobenzene group that switches from trans to cis geometry in blue light. This isomerization alters the electronic properties of the molecules, increasing their affinity for a zinc ion in the active site of HDACs. Cultured cancer cells treated with one of the inhibitors, BG14, had similar gene expression profiles as ones treated with a known HDAC inhibitor, but only when the BG14-treated cells were hit with blue light. This activity demonstrated that the designed molecules function as light-controlled switches for the epigenetic regulators.

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