Active genes are tri-methylated at K4 of histone H3

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Lysine methylation of histones in vivo occurs in three states: mono-, di- and tri-methyl1. Histone H3 has been found to be di-methylated at lysine 4 (K4) in active euchromatic regions but not in silent heterochromatic sites2. Here we show that the Saccharomyces cerevisiae Set1 protein can catalyse di- and tri-methylation of K4 and stimulate the activity of many genes. Using antibodies that discriminate between the di- and tri-methylated state of K4 we show that di-methylation occurs at both inactive and active euchromatic genes, whereas tri-methylation is present exclusively at active genes. It is therefore the presence of a tri-methylated K4 that defines an active state of gene expression. These findings establish the concept of methyl status as a determinant for gene activity and thus extend considerably the complexity of histone modifications.

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Figure 1: Set1 methylates histone H3.
Figure 2: Specific antibodies discriminate between H3 K4 di-methyl and tri-methyl.
Figure 3: Set1 methylation is required for full gene expression.
Figure 4: Di-methylation and tri-methylation of H3 K4 correlates with transcriptionally active genes.


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We thank V. Geli for the gift of the UCC1001 wild-type strain, set1::HIS3 and set1::kan strains, and K. Nightingale for the gift of recombinant wild-type and tail-less H3 histone. This work was funded by an EU grant to H.S.R., an EMBO long-term fellowship to R.S. and a Cancer Research UK grant to T.K.

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Correspondence to Tony Kouzarides.

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T.K. is a founding member of Abcam, the company that has made the tri-methylated K4 histone H3 antibody.

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Santos-Rosa, H., Schneider, R., Bannister, A. et al. Active genes are tri-methylated at K4 of histone H3. Nature 419, 407–411 (2002) doi:10.1038/nature01080

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