Targeting Chromatin Disruption: Transcription Regulators that Acetylate Histones

Abstract

The discovery that a transcriptional regulator GCN5p is a histone acetyltransferase (Brownell et al. 1996xBrownell, J.E., Zhou, J., Ranalli, T., Kobayashi, R., Edmondson, D.G., Roth, S.Y., and Allis, C.D. Cell. 1996; 84Abstract | Full Text | Full Text PDF | PubMed | Scopus (1023)See all ReferencesBrownell et al. 1996) provides a new set of possible mechanisms by which transcription might be regulated. These mechanisms lead to a model for the targeted disruption of chromatin structure that requires the selective recruitment of GCN5p to a particular regulatory element. It is of course possible that GCN5p acetylates transcription components other than histones, or that the acetyltransferase activity has no influence on transcription, however, these possibilities seem unlikely in view of the known properties of the Tetrahymena p55 protein and the strong correlation between histone acetylation and transcription.Several observations indicate that there may be other targeted transcriptional regulators in addition to GCN5p with the capacity to modify histones. GCN5p is not an essential gene for viability in yeast (Georgakopoulos and Thireos 1992xGeorgakopoulos, T. and Thireos, G. EMBO J. 1992; 11: 4145–4152PubMedSee all ReferencesGeorgakopoulos and Thireos 1992) and the Tetrahymena histone acetyltransferase appears to selectively modify histone H3 (Brownell et al. 1996xBrownell, J.E., Zhou, J., Ranalli, T., Kobayashi, R., Edmondson, D.G., Roth, S.Y., and Allis, C.D. Cell. 1996; 84Abstract | Full Text | Full Text PDF | PubMed | Scopus (1023)See all ReferencesBrownell et al. 1996). Several distinct patterns of histone acetylation have been defined for individual core histones. Thus, other transcriptional regulators might acetylate different core histones with distinct specificities for different lysine residues in the N-terminal tails. Such capacity for covalent modification through acetylation emerges as a novel function for the transcriptional machinery.The question why mutation of the N-terminal tail domains of individual histones has specific consequences for the expression of particular genes (Grunstein et al. 1992xSee all ReferencesGrunstein et al. 1992) is answered by the specificity and targeting of acetylation patterns as a component of the transcription process. The interaction of the histone acetyltransferase with regulators that themselves interact with DNA binding proteins explains the targeting phenomenon. The potential specificity of histone acetylation patterns directed by a particular acetyltransferase, or the specific requirements for acetylation at an individual promoter can account for why mutations in the N-terminal tails of the histones influence transcription of a restricted set of genes. What emerges from these observations is the opportunity for chromatin structure to be precisely modulated through highly regulated reversible mechanisms. Such modifications might be a prerequisite for transcriptional activation.The recognition that transcription factors might function through enzymatic activities that modulate chromatin structure is important for our understanding of both transcriptional regulation per se and the role of chromatin structure in the nucleus. Gene regulation in eukaryotes involves substantial communication between architectural proteins such as histones and the transcriptional machinery itself.