Discovery of the first chemical inhibitor of histone demethylation
The study of post-translational modification of histone tails represents one of the largest areas of research in the field of epigenetics. An improved understanding of how these modifications are added, recognized, and removed is essential to understand the mechanisms underlying epigenetic-based human diseases and to allow for the discovery of new medicine to treat these disorders. One way to probe the activity of the enzymes and proteins responsible for chromatin modification is to use chemical inhibitors of their activity. While this approach has tremendous potential to uncover how histone modification is regulated, there is currently a lack of molecules that specifically inhibit modifying enzymes, thus hindering its utility. In an article recently published in Nature, Kruidenier et al. described the discovery of the first drug that can selectively and potently inhibit a specific class of histone demethylase enzymes.
The authors solved the crystal structure of Jumonji C domain-containing protein 3 (JMJD3), which is a member of the lysine demethylase 6 (KDM6) subfamily of histone demethylases. These enzymes specifically demethylate histone H3 trimethylated on lysine residue 27 (H3K27me3), which is a mark of repressed, transcriptionally silent chromatin. They used the high-resolution structure to perform and optimize a screen for small molecule inhibition of JMJD3. The molecule they discovered was named GSK-J1, and this compound specifically inhibited JMJD3 and the closely related Ubiquitously Transcribed X chromosome tetratricopeptide repeat protein (UTX) in several biochemical assays. GSK-J1 did not show activity against other demethylases in the JMJ family, nor any other enzymes tested, such as several kinases and histone deacetylases, demonstrating that its activity was very specific. Furthermore, an immobilized version of GSK-J1 specifically bound JMJD3 and UTX in cell lysates and cells treated with the compound exhibited increased levels of H3K27me3, indicating that JMJD3 was inhibited by GSK-J1.
JMJD3 is known to mediate an inflammatory response in cells exposed to lipopolysaccharide (LPS), but the mechanism of this activity was not known. In a primary macrophage culture, the authors demonstrated that treatment with a GSK-J1 derivative inhibited the expression of many LPS-induced inflammatory cytokines, notably including tumor necrosis factor-α (TNF-α). The authors performed chromatin immunoprecipitation experiments to demonstrate that drug treatment resulted in a loss of the LPS-induced reduction of H3K27me3 at the promoter for the TNF-α gene, as well as decreased recruitment of RNA polymerase II, suggesting that JMJD3 normally contributes to inducing inflammation in response to LPS by removing the inhibitory H3K27me3 chromatin mark at the promoters of cytokine genes, thus allowing their transcription.
This report is the first example of a specific histone demethylase inhibitor, and demonstrates that small molecule inhibitors of histone-modifying enzymes have great potential to improve our understanding of epigenetic regulation of gene expression, as well as to be novel classes of drugs to treat epigenetic-based human diseases. What do you think this discovery means for the future of medicine?
Kruidenier L. et al. (2012) A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature. doi:10.1038/nature11262 (published online July 26, 2012).