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Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast

Nature volume 418, pages 104–108 (2002)Cite this article

Abstract

In eukaryotes, the DNA of the genome is packaged with histone proteins to form nucleosomal filaments, which are, in turn, folded into a series of less well understood chromatin structures1. Post-translational modifications of histone tail domains modulate chromatin structure and gene expression2,3,4. Of these, histone ubiquitination is poorly understood. Here we show that the ubiquitin-conjugating enzyme Rad6 (Ubc2) mediates methylation of histone H3 at lysine 4 (Lys 4) through ubiquitination of H2B at Lys 123 in yeast (Saccharomyces cerevisiae). Moreover, H3 (Lys 4) methylation is abolished in the H2B-K123R mutant, whereas H3-K4R retains H2B (Lys 123) ubiquitination. These data indicate a unidirectional regulatory pathway in which ubiquitination of H2B (Lys 123) is a prerequisite for H3 (Lys 4) methylation. We also show that an H2B-K123R mutation perturbs silencing at the telomere, providing functional links between Rad6-mediated H2B (Lys 123) ubiquitination, Set1-mediated H3 (Lys 4) methylation, and transcriptional silencing. Thus, these data reveal a pathway leading to gene regulation through concerted histone modifications on distinct histone tails. We refer to this as ‘trans-tail’ regulation of histone modification, a stated prediction of the histone code hypothesis5,6.

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Figure 1: The ubiquitin-conjugating enzyme Rad6 is important for H3 (Lys 4) methylation.
Figure 2: Ubiquitination of H2B at Lys 123 by Rad6 is a prerequisite for H3 (Lys 4) methylation.
Figure 3: Ubiquitinated Flag-H2B is associated with chromatin containing methylated (Lys 4) H3.
Figure 4: H2B Lys 123 is important for telomeric silencing.

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Acknowledgements

We thank M. Bryk, M. Hampsey, M. A. Osley, M. Smith and F. Winston for providing yeast strains and DNA constructs, and J. Hoeijmakers and H. Roest for providing mouse HR6A and HR6B cDNA clones. S. Cheung is gratefully acknowledged for providing advice and reagents for ChIP assays. We thank P. and S. Cheung for critical reading of the manuscript, and current Allis laboratory members for discussions and technical advice. This research was supported by grants from the National Institutes of Health to C.D.A. Z.-W.S. is supported by a postdoctoral cancer training grant from the University of Virginia Cancer Center.

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  1. Department of Biochemistry and Molecular Genetics, University of Virginia Health System, Charlottesville, Virginia, 22908-0733, USA

    Zu-Wen Sun & C. David Allis

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Correspondence to C. David Allis.

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Sun, ZW., Allis, C. Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature 418, 104–108 (2002). https://doi.org/10.1038/nature00883

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