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Active genes are tri-methylated at K4 of histone H3

Abstract

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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References

  1. Strahl, B. D., Ohba, R., Cook, R. G. & Allis, C. D. Methylation of histone H3 at lysine 4 is highly conserved and correlates with transcriptionally active nuclei in Tetrahymena. Proc. Natl Acad. Sci. USA 96, 14967–14972 (1999)

    Article  ADS  CAS  Google Scholar 

  2. Noma, K., Allis, C. D. & Grewal, S. I. Transitions in distinct histone H3 methylation patterns at the heterochromatin domain boundaries. Science 293, 1150–1155 (2001)

    Article  CAS  Google Scholar 

  3. Cheung, P., Allis, C. D. & Sassone-Corsi, P. Signaling to chromatin through histone modifications. Cell 103, 263–271 (2000)

    Article  CAS  Google Scholar 

  4. Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000)

    Article  ADS  CAS  Google Scholar 

  5. Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 579–580 (2000)

    Article  Google Scholar 

  6. Bannister, A. J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001)

    Article  ADS  CAS  Google Scholar 

  7. Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001)

    Article  ADS  CAS  Google Scholar 

  8. Roguev, A. et al. The Saccharomyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone 3 lysine 4. EMBO J. 20, 7137–7148 (2001)

    Article  CAS  Google Scholar 

  9. Briggs, S. D. et al. Histone H3 lysine 4 methylation is mediated by Set1 and required for cell growth and rDNA silencing in Saccharomyces cerevisiae. Genes Dev. 15, 3286–3295 (2001)

    Article  CAS  Google Scholar 

  10. Nislow, C., Ray, E. & Pillus, L. SET1, a yeast member of the trithorax family, functions in transcriptional silencing and diverse cellular processes. Mol. Biol. Chem. 8, 2421–2436 (1997)

    CAS  Google Scholar 

  11. Krogan, N. J. et al. COMPASS: a complex of proteins associated with a trithorax-related SET domain protein. Proc. Natl Acad. Sci. 98, 12902–12907 (2001)

    Article  ADS  Google Scholar 

  12. Bryk, M. et al. Evidence that Set1, a factor required for methylation of histone H3, regulates rDNA silencing in S. cerevisiae by a Sir2-independent mechanism. Curr. Biol. 12, 165–170 (2002)

    Article  CAS  Google Scholar 

  13. Krogan, N. J. et al. COMPASS, a histone H3 (Lysine 4) methyltransferase required for telomeric silencing of gene expression. J. Biol. Chem. 13, 10753–10755 (2002)

    Article  Google Scholar 

  14. Litt, M. D., Simpson, M., Gaszner, M., Allis, C. D. & Felsenfeld, G. Correlation between histone lysine methylation and developmental changes at the chicken β-globin locus. Science 293, 2453–2455 (2001)

    Article  ADS  CAS  Google Scholar 

  15. Bernstein, B. E. et al. Methylation of histone H3 Lys 4 in coding regions of active genes. Proc. Natl Acad. Sci. USA 99, 8695–8697 (2002)

    Article  ADS  CAS  Google Scholar 

  16. Siniossoglou, S. et al. A novel complex of nucleoporins, which includes Sec13p and a Sec13p homolog, is essential for normal nuclear pores. Cell 84, 265–275 (1996)

    Article  CAS  Google Scholar 

  17. Carroll, A. S., Bishop, A. C., DeRisi, J. L., Shokat, K. M. & O'Shea, E. K. Chemical inhibition of the Pho85 cyclin-dependent kinase reveals a role in the environmental stress response. Proc. Natl Acad. Sci. USA 98, 12578–12583 (2001)

    Article  ADS  CAS  Google Scholar 

  18. DeRisi, J. L., Iyer, V. R. & Brown, P. O. Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 278, 680–686 (1997)

    Article  ADS  CAS  Google Scholar 

  19. Hughes, T. R. et al. Functional discovery via a compendium of expression profiles. Cell 102, 109–126 (2000)

    Article  CAS  Google Scholar 

  20. Kent, N. A., Karabetsou, N., Politis, P. K. & Mellor, J. In vivo chromatin remodeling by yeast ISWI homologs Isw1p and Isw2p. Genes Dev. 15, 619–626 (2001)

    Article  CAS  Google Scholar 

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Acknowledgements

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). https://doi.org/10.1038/nature01080

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