Histone Acetyltransferase Complexes Can Mediate Transcriptional Activation by the Major Glucocorticoid Receptor Activation Domain

Abstract

Previous studies have shown that the Ada adapter proteins are important for glucocorticoid receptor (GR)-mediated gene activation in yeast. The N-terminal transactivation domain of GR, τ1, is dependent upon Ada2, Ada3, and Gcn5 for transactivation in vitro and in vivo. Using in vitro techniques, we demonstrate that the GR-τ1 interacts directly with the native Ada containing histone acetyltransferase (HAT) complex SAGA but not the related Ada complex. Mutations in τ1 that reduce τ1 transactivation activity in vivo lead to a reduced binding of τ1 to the SAGA complex and conversely, mutations increasing the transactivation activity of τ1 lead to an increased binding of τ1 to SAGA. In addition, the Ada-independent NuA4 HAT complex also interacts with τ1. GAL4-τ1-driven transcription from chromatin templates is stimulated by SAGA and NuA4 in an acetyl coenzyme A-dependent manner. Low-activity τ1 mutants reduce SAGA- and NuA4-stimulated transcription while high-activity τ1 mutants increase transcriptional activation, specifically from chromatin templates. Our results demonstrate that the targeting of native HAT complexes by the GR-τ1 activation domain mediates transcriptional stimulation from chromatin templates.

ACKNOWLEDGMENTS

We thank David Steger, Sam John, and Anton Eberharter for providing reagents and for valuable discussions.

P.A.G. is funded by postdoctoral fellowship PF-98-017-01-GMC from the American Cancer Society. J.L.W. is an Associate Investigator of the Howard Hughes Medical Institute. This work was supported by grants from the National Institute of General Medical Sciences (awarded to J.L.W.), the Swedish Natural Sciences Research Council (awarded to A.P.H.W.), the Swedish Medical Research Council (awarded to J.-Å.G. [13x-2819] and A.E.W. [K98-03RM-12413]), and the Erik and Edith Fernströms Foundation (awarded to A.E.W.).