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Biological Chemistry

Study of Histone Methylation Will Benefit from Chemical Perspective

by AMANDA YARNELL, C&EN WASHINGTON
May 2, 2005 | A version of this story appeared in Volume 83, Issue 18

Chemists may not themselves be unraveling the intricacies of histone methylation, but their perspective and skills may prove valuable to the task.

For example, the hunt for histone demethylases will be helped by fluorescent cellular reporters of histone methylation developed by chemists Alice Y. Ting, Chi-Wang Lin, and Cindy Y. Jao at Massachusetts Institute of Technology (J. Am. Chem. Soc. 2004, 126, 5982).

The reporters are based on a fusion protein in which a histone-derived peptide containing a methylation-prone lysine residue is joined via a flexible linker to a methyllysine-binding protein. This fusion construct is sandwiched between a pair of fluorescent proteins. When the lysine is methylated, the flanking fluorescent proteins undergo fluorescence resonance energy transfer. In the presence of the appropriate histone demethylase, the protein undergoes a conformational change that causes an easily detected change in fluorescence.

This system "can be used to conduct highly sensitive and specific high-throughput screens for histone demethylase activity, either in vitro or in live cells," Ting says. She says her lab has distributed the constructs to labs hoping to perform such screens.

Questions surrounding the biological role of histone methylation also could benefit from a chemical perspective. For example, "there's a real lack of information about which protein methylarginine derivatives actually exist in vivo," says Scott A. Coonrod of Cornell University's Weill Medical College. "The only evidence for the existence of protein dimethylarginine comes from the use of modification-specific antibodies," he says, noting that his team has observed that antibodies created to detect dimethylarginine are in fact unable to distinguish between dimethyl- and monomethylarginine. "Only histone monomethylarginine has been detected in cells by mass spectrometry. Detection of methylarginine derivatives is an area that really needs exploring by chemists."

Finally, Yang J. Shi of Harvard Medical School suggests that, like enzymes that remove acetyl groups from histone tails, histone demethylases could prove to be valuable drug targets for cancer. As a step in that direction, his group hopes to find small molecules that might modulate the activity of the histone demethylase LSD1.

MORE ON THIS STORY

Study Of Histone Methylation Will Benefit From Chemical Perspective
Study Of Histone Methylation Will Benefit From Chemical Perspective

HISTONE METHYLATION PROVES REVERSIBLE
Cells use transient methylation, demethylation to control access to tightly packed genome

 

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