Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Originally published in Science Express on 30 August 2007
Science 19 October 2007:
Vol. 318. no. 5849, pp. 447 - 450
DOI: 10.1126/science.1149042
Prev | Table of Contents | Next

Reports

Demethylation of H3K27 Regulates Polycomb Recruitment and H2A Ubiquitination

Min Gyu Lee,1 Raffaella Villa,2 Patrick Trojer,3 Jessica Norman,1 Kai-Ping Yan,1 Danny Reinberg,3 Luciano Di Croce,2 Ramin Shiekhattar1,2*

Methylation of histone H3 lysine 27 (H3K27) is a posttranslational modification that is highly correlated with genomic silencing. Here we show that human UTX, a member of the Jumonji C family of proteins, is a di- and trimethyl H3K27 demethylase. UTX occupies the promoters of HOX gene clusters and regulates their transcriptional output by modulating the recruitment of polycomb repressive complex 1 and the monoubiquitination of histone H2A. Moreover, UTX associates with mixed-lineage leukemia (MLL) 2/3 complexes, and during retinoic acid signaling events, the recruitment of the UTX complex to HOX genes results in H3K27 demethylation and a concomitant methylation of H3K4. Our results suggest a concerted mechanism for transcriptional activation in which cycles of H3K4 methylation by MLL2/3 are linked with the demethylation of H3K27 through UTX.

1 The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
2 Institució Catalana de Recerca i Estudis Avançats and Centre de Regulació Genòmica, Barcelona, Spain.
3 Howard Hughes Medical Institute, Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA.

* To whom correspondence should be addressed. E-mail: ramin.shiekhattar{at}crg.es

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Recruitment of Polycomb group complexes and their role in the dynamic regulation of cell fate choice.
B. Schuettengruber and G. Cavalli (2009)
Development 136, 3531-3542
   Abstract »    Full Text »    PDF »
Epigenetic regulation of the alternatively activated macrophage phenotype.
M. Ishii, H. Wen, C. A. S. Corsa, T. Liu, A. L. Coelho, R. M. Allen, W. F. Carson IV, K. A. Cavassani, X. Li, N. W. Lukacs, et al. (2009)
Blood 114, 3244-3254
   Abstract »    Full Text »    PDF »
ASCOM Controls Farnesoid X Receptor Transactivation through Its Associated Histone H3 Lysine 4 Methyltransferase Activity.
D.-H. Kim, J. Lee, B. Lee, and J. W. Lee (2009)
Mol. Endocrinol. 23, 1556-1562
   Abstract »    Full Text »    PDF »
Nucleosomes are well positioned in exons and carry characteristic histone modifications.
R. Andersson, S. Enroth, A. Rada-Iglesias, C. Wadelius, and J. Komorowski (2009)
Genome Res. 19, 1732-1741
   Abstract »    Full Text »    PDF »
CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila Polycomb silencing.
F. Tie, R. Banerjee, C. A. Stratton, J. Prasad-Sinha, V. Stepanik, A. Zlobin, M. O. Diaz, P. C. Scacheri, and P. J. Harte (2009)
Development 136, 3131-3141
   Abstract »    Full Text »    PDF »
Alterations of histone modifications by cobalt compounds.
Q. Li, Q. Ke, and M. Costa (2009)
Carcinogenesis 30, 1243-1251
   Abstract »    Full Text »    PDF »
A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4.
J. Lee, D.-H. Kim, S. Lee, Q.-H. Yang, D. K. Lee, S.-K. Lee, R. G. Roeder, and J. W. Lee (2009)
PNAS 106, 8513-8518
   Abstract »    Full Text »    PDF »
The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence.
K. Agger, P. A.C. Cloos, L. Rudkjaer, K. Williams, G. Andersen, J. Christensen, and K. Helin (2009)
Genes & Dev. 23, 1171-1176
   Abstract »    Full Text »    PDF »
Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS.
M. Barradas, E. Anderton, J. C. Acosta, S. Li, A. Banito, M. Rodriguez-Niedenfuhr, G. Maertens, M. Banck, M.-M. Zhou, M. J. Walsh, et al. (2009)
Genes & Dev. 23, 1177-1182
   Abstract »    Full Text »    PDF »
Crucial Roles for Interactions between MLL3/4 and INI1 in Nuclear Receptor Transactivation.
S. Lee, D.-H. Kim, Y. H. Goo, Y. C. Lee, S.-K. Lee, and J. W. Lee (2009)
Mol. Endocrinol. 23, 610-619
   Abstract »    Full Text »    PDF »
Identification and Characterization of a Novel Nuclear Protein Complex Involved in Nuclear Hormone Receptor-mediated Gene Regulation.
S. Garapaty, C.-F. Xu, P. Trojer, M. A. Mahajan, T. A. Neubert, and H. H. Samuels (2009)
J. Biol. Chem. 284, 7542-7552
   Abstract »    Full Text »    PDF »
Developmental roles of the histone lysine demethylases.
A. Nottke, M. P. Colaiacovo, and Y. Shi (2009)
Development 136, 879-889
   Abstract »    Full Text »    PDF »
Loss of Mll5 results in pleiotropic hematopoietic defects, reduced neutrophil immune function, and extreme sensitivity to DNA demethylation.
M. Heuser, D. B. Yap, M. Leung, T. R. de Algara, A. Tafech, S. McKinney, J. Dixon, R. Thresher, B. Colledge, M. Carlton, et al. (2009)
Blood 113, 1432-1443
   Abstract »    Full Text »    PDF »
Molecular Regulation of H3K4 Trimethylation by Wdr82, a Component of Human Set1/COMPASS.
M. Wu, P. F. Wang, J. S. Lee, S. Martin-Brown, L. Florens, M. Washburn, and A. Shilatifard (2008)
Mol. Cell. Biol. 28, 7337-7344
   Abstract »    Full Text »    PDF »
Targeted inactivation of MLL3 histone H3-Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis.
J. Lee, P. K. Saha, Q.-H. Yang, S. Lee, J. Y. Park, Y. Suh, S.-K. Lee, L. Chan, R. G. Roeder, and J. W. Lee (2008)
PNAS 105, 19229-19234
   Abstract »    Full Text »    PDF »
Regulation of Stem Cell Differentiation by Histone Methyltransferases and Demethylases.
D. Pasini, A.P. Bracken, K. Agger, J. Christensen, K. Hansen, P.A.C. Cloos, and K. Helin (2008)
Cold Spring Harb Symp Quant Biol
   Abstract »    PDF »
Coordinated but physically separable interaction with H3K27-demethylase and H3K4-methyltransferase activities are required for T-box protein-mediated activation of developmental gene expression.
S. A. Miller, A. C. Huang, M. M. Miazgowicz, M. M. Brassil, and A. S. Weinmann (2008)
Genes & Dev. 22, 2980-2993
   Abstract »    Full Text »    PDF »
dKDM2 couples histone H2A ubiquitylation to histone H3 demethylation during Polycomb group silencing.
A. Lagarou, A. Mohd-Sarip, Y. M. Moshkin, G. E. Chalkley, K. Bezstarosti, J. A.A. Demmers, and C. P. Verrijzer (2008)
Genes & Dev. 22, 2799-2810
   Abstract »    Full Text »    PDF »
Arsenite alters global histone H3 methylation.
X. Zhou, H. Sun, T. P. Ellen, H. Chen, and M. Costa (2008)
Carcinogenesis 29, 1831-1836
   Abstract »    Full Text »    PDF »
Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3.
G. L. Sen, D. E. Webster, D. I. Barragan, H. Y. Chang, and P. A. Khavari (2008)
Genes & Dev. 22, 1865-1870
   Abstract »    Full Text »    PDF »
Activating Signal Cointegrator-2 Is an Essential Adaptor to Recruit Histone H3 Lysine 4 Methyltransferases MLL3 and MLL4 to the Liver X Receptors.
S. Lee, J. Lee, S.-K. Lee, and J. W. Lee (2008)
Mol. Endocrinol. 22, 1312-1319
   Abstract »    Full Text »    PDF »
Cooperation between EZH2, NSPc1-mediated histone H2A ubiquitination and Dnmt1 in HOX gene silencing.
X. Wu, Y. Gong, J. Yue, B. Qiang, J. Yuan, and X. Peng (2008)
Nucleic Acids Res. 36, 3590-3599
   Abstract »    Full Text »    PDF »
Spermatogenesis-specific association of SMCY and MSH5..
C. Akimoto, H. Kitagawa, T. Matsumoto, and S. Kato (2008)
Genes Cells 13, 623-633
   Abstract »    Full Text »    PDF »
SWI/SNF Mediates Polycomb Eviction and Epigenetic Reprogramming of the INK4b-ARF-INK4a Locus.
S. K. Kia, M. M. Gorski, S. Giannakopoulos, and C. P. Verrijzer (2008)
Mol. Cell. Biol. 28, 3457-3464
   Abstract »    Full Text »    PDF »
The LIM Protein AJUBA Recruits Protein Arginine Methyltransferase 5 To Mediate SNAIL-Dependent Transcriptional Repression.
Z. Hou, H. Peng, K. Ayyanathan, K.-P. Yan, E. M. Langer, G. D. Longmore, and F. J. Rauscher III (2008)
Mol. Cell. Biol. 28, 3198-3207
   Abstract »    Full Text »    PDF »
Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and Polycomb-Repressive Complex 2.
D. Pasini, K. H. Hansen, J. Christensen, K. Agger, P. A.C. Cloos, and K. Helin (2008)
Genes & Dev. 22, 1345-1355
   Abstract »    Full Text »    PDF »
Changes in the Distributions and Dynamics of Polycomb Repressive Complexes during Embryonic Stem Cell Differentiation.
X. Ren, C. Vincenz, and T. K. Kerppola (2008)
Mol. Cell. Biol. 28, 2884-2895
   Abstract »    Full Text »    PDF »
Characterization of Drosophila melanogaster JmjC+N histone demethylases.
M. Lloret-Llinares, C. Carre, A. Vaquero, N. de Olano, and F. Azorin (2008)
Nucleic Acids Res. 36, 2852-2863
   Abstract »    Full Text »    PDF »
Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease.
P. A.C. Cloos, J. Christensen, K. Agger, and K. Helin (2008)
Genes & Dev. 22, 1115-1140
   Abstract »    Full Text »    PDF »
Sex-Specific Differences in Expression of Histone Demethylases Utx and Uty in Mouse Brain and Neurons.
J. Xu, X. Deng, R. Watkins, and C. M. Disteche (2008)
J. Neurosci. 28, 4521-4527
   Abstract »    Full Text »    PDF »
Mass spectrometry identifies and quantifies 74 unique histone H4 isoforms in differentiating human embryonic stem cells.
D. Phanstiel, J. Brumbaugh, W. T. Berggren, K. Conard, X. Feng, M. E. Levenstein, G. C. McAlister, J. A. Thomson, and J. J. Coon (2008)
PNAS 105, 4093-4098
   Abstract »    Full Text »    PDF »
Drosophila UTX Is a Histone H3 Lys27 Demethylase That Colocalizes with the Elongating Form of RNA Polymerase II.
E. R. Smith, M. G. Lee, B. Winter, N. M. Droz, J. C. Eissenberg, R. Shiekhattar, and A. Shilatifard (2008)
Mol. Cell. Biol. 28, 1041-1046
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)