Histone acetylation and transcriptional regulatory mechanisms

More than 30 years ago, Vincent Allfrey proposed that histone acetylation was associated with transcriptional activity in eukaryotic cells (Allfrey et al. 1964; Pogo et al. 1966). Subsequently, acetylated core histones were shown to preferentially associate with transcriptionally active chromatin (Sealy and Chalkley 1978; Vidali et al. 1978; Hebbes et al. 1988). Acetylation occurs at lysine residues on the amino-terminal tails of the histones, thereby neutralizing the positive charge of the histone tails and decreasing their affinity for DNA (Hong et al. 1993). As a consequence, histone acetylation alters nucleosomal conformation (Norton et al. 1989), which can increase the accessibility of transcriptional regulatory proteins to chromatin templates (Lee et al. 1993; Vettese-Dadey et al. 1996). Taken together, these observations suggested how histone acetylation could result in increased transcriptional activity in vivo. However, there was essentially no information about the cause and effect relationship between histone acetylation and transcriptional activity or about the underlying molecular mechanisms. A mechanistic and physiologically relevant connection between histone acetylation and transcriptional regulation was initially provided by two independent lines of evidence. First, yeast cells unable to acetylate the histone H4 tail because of mutations of the target lysine residues show altered patterns of transcription (Durrin et al. 1991). However, these mutations broadly affect chromatin structure in vivo, and hence are likely to influence other molecular processes involving DNA (e.g., DNA replication and repair, recombination, chromosome segregation). Second, treatment of mammalian cells with potent inhibitors of histone deacetylase activity such as trapoxin or trichostatin A resulted in increased expression of a variety of genes (Yoshida et al. 1995). However, these drugs might inhibit other cellular targets, and they affect a variety of cellular processes, including cell proliferation, apoptosis, differentiation, and DNA synthesis. Although these observations were suggestive, understanding of the relationship between chromatin structure and transcription regulation was hampered significantly by a lack of knowledge about the enzymes that acetylate and deacetylate histones. In the past 2 years, our understanding of the causal relationship between histone acetylation and gene expression has been enhanced dramatically by the identification of proteins with intrinsic histone acetylase and deacetylase activity (Brownell et al. 1996; for recent reviews, see Grunstein 1997; Pazin and Kadonaga 1997; Wade et al. 1997). Of particular significance, some of these enzymes had been identified previously as components of the RNA polymerase II (Pol II) transcription machinery itself, proteins that associate with transcriptional regulatory factors, or proteins that positively or negatively affect transcription in vivo. These discoveries have led to a major paradigm shift. It is now clear that chromatin structure and modification can not be viewed as a process that is independent of transcriptional initiation, that is, chromatin is not simply a structure that serves to compact DNA in the nucleus and provide a relatively passive substrate for the action of transcription factors. Instead, histone acetylases and deacetylases provide a critical link between chromatin structure and transcriptional output, and this link is now accessible to experimental intervention. This review will focus on molecular mechanisms by which histone acetylation affects transcriptional activity in living cells.