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Histone demethylation by a family of JmjC domain-containing proteins

Abstract

Covalent modification of histones has an important role in regulating chromatin dynamics and transcription. Whereas most covalent histone modifications are reversible, until recently it was unknown whether methyl groups could be actively removed from histones. Using a biochemical assay coupled with chromatography, we have purified a novel JmjC domain-containing protein, JHDM1 (JmjC domain-containing histone demethylase 1), that specifically demethylates histone H3 at lysine 36 (H3-K36). In the presence of Fe(ii) and α-ketoglutarate, JHDM1 demethylates H3-methyl-K36 and generates formaldehyde and succinate. Overexpression of JHDM1 reduced the level of dimethyl-H3-K36 (H3K36me2) in vivo. The demethylase activity of the JmjC domain-containing proteins is conserved, as a JHDM1 homologue in Saccharomyces cerevisiae also has H3-K36 demethylase activity. Thus, we identify the JmjC domain as a novel demethylase signature motif and uncover a protein demethylation mechanism that is conserved from yeast to human.

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Figure 1: Identification of a demethylase activity in HeLa cells.
Figure 2: Purification and identification of a histone demethylase activity.
Figure 3: Characterization of the histone demethylase JHDM1A/FBXL11.
Figure 4: Flag–JHDM1A-mediated histone demethylation generates formaldehyde and succinate.
Figure 5: The S. cerevisiae JHDM1 homologue exhibits H3-K36 demethylase activity.

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Acknowledgements

We thank L. Lacomis and G. Boysen for help with mass spectrometry; B. Strahl, T. Jenuwein, Y. Shinkai and A. Verreault for reagents; R. Cao for the EZH2 complex; and R. Klose for critical reading of the manuscript. This work was supported by NIH grants to Y.Z., P.T. and C.H.B. Y.Z. is an Investigator of the Howard Hughes Medical Institute. Author Contributions Y.Z. designed the experimental strategy and wrote the paper; Y.T. worked out the details of the assay and performed most of the experiments; J.F. analysed the yeast protein; H.E.-B., M.E.W., C.H.B. and P.T. performed mass spectrometric analysis.

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Correspondence to Yi Zhang.

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Tsukada, Yi., Fang, J., Erdjument-Bromage, H. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006). https://doi.org/10.1038/nature04433

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