Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases
- *Nuclear Receptor Biology Section, Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and
- †Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702
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Edited by Steven Henikoff, Fred Hutchinson Cancer Research Center, Seattle, WA, and approved October 5, 2007 (received for review August 2, 2007)
Abstract
Covalent modifications of histones, such as acetylation and methylation, play important roles in the regulation of gene expression. Histone lysine methylation has been implicated in both gene activation and repression, depending on the specific lysine (K) residue that becomes methylated and the state of methylation (mono-, di-, or trimethylation). Methylation on K4, K9, and K36 of histone H3 has been shown to be reversible and can be removed by site-specific demethylases. However, the enzymes that antagonize methylation on K27 of histone H3 (H3K27), an epigenetic mark important for embryonic stem cell maintenance, Polycomb-mediated gene silencing, and X chromosome inactivation have been elusive. Here we show the JmjC domain-containing protein UTX (ubiquitously transcribed tetratricopeptide repeat, X chromosome), as well as the related JMJD3 (jumonji domain containing 3), specifically removes methyl marks on H3K27 in vitro. Further, the demethylase activity of UTX requires a catalytically active JmjC domain. Finally, overexpression of UTX and JMJD3 leads to reduced di- and trimethylation on H3K27 in cells, suggesting that UTX and JMJD3 may function as H3K27 demethylases in vivo. The identification of UTX and JMJD3 as H3K27-specific demethylases provides direct evidence to indicate that similar to methylation on K4, K9, and K36 of histone H3, methylation on H3K27 is also reversible and can be dynamically regulated by site-specific histone methyltransferases and demethylases.
Footnotes
- ‡To whom correspondence should be addressed. E-mail: kaig{at}niddk.nih.gov
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Author contributions: S.H. and Y.-W.C. contributed equally to this work; S.H. and K.G. designed research; S.H., Y.-W.C., L.-R.Y., and H.Y. performed research; T.D.V. contributed new reagents/analytic tools; S.H., Y.-W.C., L.-R.Y., and K.G. analyzed data; and K.G. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0707292104/DC1.
