PHDs Recognize Histone Cues

Science's STKE  11 Jul 2006:
Vol. 2006, Issue 343, pp. tw223
DOI: 10.1126/stke.3432006tw223

Active genes can be detected by cellular proteins because the active genes have covalent modification of associated chromatin proteins. In particular, triple methylation of lysine 4 of histone H3 (H3K4me3) is associated with all active genes. The modified histone can be recognized by proteins containing a chromodomain, which preferentially binds H3K4me3. A group of four papers in this week's Nature now reveal the PHD (plant homeodomain) domain as another protein domain that specifically recognizes H3K4me3. Wysocka et al. show that the PHD domain in the BPTF protein, a subunit of the nucleosome remodeling factor called NURF, recruits the factor to chromatin containing trimethylated H3. The interaction appears to be functionally important, because inhibition of histone modification (achieved by injection of Xenopus embryos with morpholino oligonucleotides to a factor required for the methylation) or depletion of BPTF caused similar developmental defects. Furthermore, the defects could be rescued by wild-type BPTF, but not by BPTF with a truncation of the PHD domain. Shi et al. also found the PHD domain to be important for recognition of methylated histone H3 in mammalian cells. They report that the tumor suppressor protein ING2 (inhibitor of growth 2) bound preferentially to histone 3 that was di- or trimethylated on lysine 4. ING2, in turn, interacts with a larger histone deacetylase complex containing other associated proteins. The deacetylase modifies nearby histones and may thereby repress transcription. The authors found that, in response to DNA damage, the ING2-containing histone deacetylase complex was recruited to the gene encoding cyclin D (a protein that promotes cell proliferation), and transcription of cyclin D was decreased. Loss of ING2 reduced the sensitivity of cells in culture to DNA damage, and sensitivity could be restored by transfection of the cells with wild-type ING2 but not with a mutant ING2 that failed to bind methylated histone H3. Two other papers detail structural aspects of the interaction of PHD domains with methylated histone H3. Becker discusses the findings in a News and Views piece.

J. Wysocka, T. Swigut, H. Xiao, T. A. Milne, S. Y. Kwon, J. Landry, M. Kauer, A. J. Tackett, B. T. Chait, P. Badenhorst, C. Wu, C. D. Allis, A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442, 86-90 (2006). [Online Journal]

X. Shi, T. Hong, K. L. Walter, M. Ewalt, E. Michishita, T. Hung, D. Carney, P. Peña, F. Lan, M. R. Kaadige, N. Lacoste, C. Cayrou, F. Davrazou, A. Saha, B. R. Cairns, D. E. Ayer, T. G. Kutateladze, Y. Shi, J. Côté, K. F. Chua, O. Gozani, ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442, 96-99 (2006). [Online Journal]

H. Li, S. Ilin, W. Wang, E. M. Duncan, J. Wysocka, C. D. Allis, D. J. Patel, Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 442, 91-95 (2006). [Online Journal]

P. V. Peña, F. Davrazou, X. Shi, K. L. Walter, V. V. Verkhusha, O. Gozani, R. Zhao, T. G. Kutateladze, Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2. Nature 442, 100-103 (2006). [Online Journal]

P. B. Becker, Gene regulation: A finger on the mark. Nature 442, 31-32 (2006). [Online Journal]