Arginine methylation at histone H3R2 controls deposition of H3K4 trimethylation

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Abstract

Modifications on histones control important biological processes through their effects on chromatin structure1,2,3. Methylation at lysine 4 on histone H3 (H3K4) is found at the 5′ end of active genes and contributes to transcriptional activation by recruiting chromatin-remodelling enzymes4,5. An adjacent arginine residue (H3R2) is also known to be asymmetrically dimethylated (H3R2me2a) in mammalian cells6, but its location within genes and its function in transcription are unknown. Here we show that H3R2 is also methylated in budding yeast (Saccharomyces cerevisiae), and by using an antibody specific for H3R2me2a in a chromatin immunoprecipitation-on-chip analysis we determine the distribution of this modification on the entire yeast genome. We find that H3R2me2a is enriched throughout all heterochromatic loci and inactive euchromatic genes and is present at the 3′ end of moderately transcribed genes. In all cases the pattern of H3R2 methylation is mutually exclusive with the trimethyl form of H3K4 (H3K4me3). We show that methylation at H3R2 abrogates the trimethylation of H3K4 by the Set1 methyltransferase. The specific effect on H3K4me3 results from the occlusion of Spp1, a Set1 methyltransferase subunit necessary for trimethylation. Thus, the inability of Spp1 to recognize H3 methylated at R2 prevents Set1 from trimethylating H3K4. These results provide the first mechanistic insight into the function of arginine methylation on chromatin.

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Figure 1: H3R2me2a associates with heterochromatin.
Figure 2: H3R2me2a enrichment at euchromatic genes is mutually exclusive with H3K4me3.
Figure 3: H3R2me2a regulates the activity of the Set1 complex towards H3K4.
Figure 4: H3R2me2a blocks the binding of Spp1 to methylated H3K4.

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Acknowledgements

We thank C. Nelson, A. Bannister and M. Christophorou for critical reading of the manuscript; S. Marguerat for helpful discussions; L. Packman and M. Weldon for assistance with protein sequencing; N. Jiang and R. Selzer for assistance with microarray analyses; and M. Gilchrist for help with displaying genomic data. This work was supported by postdoctoral fellowship grants to A.K. from the European Molecular Biology Organization (EMBO) and Marie Curie. The T.K. laboratory is funded by grants from Cancer Research UK (CRUK) and the 6th Research Framework Programme of the European Union (Epitron and Heroic). The microarray data sets are available from GEO (Gene Expression Omnibus) under accession number GSE8626, and from http://www.gurdon.cam.ac.uk/%7Ekouzarideslab/H3R2methylation.html

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Correspondence to Tony Kouzarides.

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Competing interests: T.K. is a director of Abcam PLC; R.D.G. and M.A.S. are employees of NimbleGen Systems, Inc.

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Kirmizis, A., Santos-Rosa, H., Penkett, C. et al. Arginine methylation at histone H3R2 controls deposition of H3K4 trimethylation. Nature 449, 928–932 (2007) doi:10.1038/nature06160

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