Transcriptional activators direct histone acetyltransferase complexes to nucleosomes

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Abstract

Transcriptional co-activators were originally identified as proteins that act as intermediaries between upstream activators and the basal transcription machinery. The discovery that co-activators such as Tetrahymena and yeast Gcn51,2, as well as human p300/CBP3,4, pCAF5, Src-16, ACTR7 and TAFII2508, can acetylate histones suggests that activators may be involved in targeting acetylation activity to promoters. Several histone deacetylases have been linked to transcriptional co-repressor proteins9, suggesting that the action of both acetylases and deacetylases is important in the regulation of many genes. Here we demonstrate the binding of two native yeast histone acetyltransferase (HAT) complexes to the herpesvirus VP16 activation domain and the yeast transcriptional activator Gcn4, and show that it is their interaction with the VP16 activation domain that targets Gal4–VP16-bound nucleosomes for acetylation. We find that Gal4–VP16-driven transcription from chromatin templates is stimulated by both HAT complexes in an acetyl CoA-dependent reaction. Our results demonstrate the targeting of native HAT complexes by a transcription-activation domain to nucleosomes in order to activate transcription.

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Figure 1: Two distinct HAT complexes interact with the VP16 activation domain and the yeast activator Gcn4.
Figure 2: SAGA and NuA4 interact specifically with the VP16 activation domain.
Figure 3: VP16 directs acetylation by SAGA and NuA4.
Figure 4: Preacetylation by SAGA and NuA4 precludes targeting by the VP16 activation domain.
Figure 5: SAGA and NuA4 stimulate Gal4–VP16-dependent transcription.

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Acknowledgements

We thank M. Green and J. Reese for the gift of GST–VP16 and GST–VP16 mutant expression plasmids, N. Barlev and S. Berger for the GST–GCN4 expression plasmid, and members of J.L.W.'s laboratory for comments on the manuscript. This work was supported by a grant from the National Institute of General Medical Sciences. P.G. is supported by a postdoctoral fellowship from the American Cancer Society; J. C. was a recipient of an MRC Centennial fellowship; A.E. holds a fellowship from the Austrian Science Foundation; D.J.S. was supported by a postdoctoral fellowship from the Cancer Research Institute; S.J. is an HHMI postdoctoral associate and J.L.W. was a Leukemia Society scholar and is currently an HHMI investigator.

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Correspondence to Jerry L. Workman.

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Utley, R., Ikeda, K., Grant, P. et al. Transcriptional activators direct histone acetyltransferase complexes to nucleosomes. Nature 394, 498–502 (1998) doi:10.1038/28886

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