Histone Acetylation and Chromatin Assembly: A Single Escort, Multiple Dances?

acetylation is carried out by HAT A activities. Until reThe compaction of eukaryotic DNA into chromatin dicently, little was known about the regulation of these rectly affects transmission of genetic material to daughHATs because none had been isolatedand cloned. Howter cells as well as the establishment of specific patever, the landmark cloning of the catalytic subunit of a terns of gene expression. How chromatin assembly is yeast HAT B (Hat1p; Kleff et al., 1995; Parthun et al., achieved and regulated in vivo is still largely a mystery. 1996) and a ciliate HAT A (highly similar to yeast Gcn5p; The fundamental building block of chromatin is the Brownell et al., 1996) has changed this situation remarknucleosome, which is comprised of an octamer of hisably (see below). In addition, Parthun et al. provide sevtoneproteins (two molecules each of histones H2A, H2B, eral important new clues into the regulation of Hat1p by H3, and H4) and 146 base pairs of DNA wound around showing that the yeast HAT B complex contains a secthe octamer. Histone synthesis and nucleosome assemond protein, Hat2p, that is highly similar to the human bly are closely tied to DNA replication in most cells, but Rb-associated protein, p48 (RbAp48, a member of an how these processes are coupled is not clear. In this evolutionarily conserved subfamily of WD-repeat proissue of Cell, Stillman and colleagues (Verreault et al., teins). Association of the Hat2p subunit with Hat1p in1996, this issue) describe the isolation of a Chromatin creases binding to the H4 amino terminus and the speAssembly Complex (CAC) from nuclei of human cells cific activity of HAT B. This finding indicates that Hat2p which assembles nucleosomes in a replication-depenis a key regulatory subunit of the HAT B complex. dent manner. Interestingly, CAC consists of the preWhat is the function of histone acetylation? Histones viously identified, three-subunit Chromatin Assembly in general possess a globular core domain, required Factor 1 (CAF-1), H3, and specific acetylated isoforms for histone–histone interactions central to nucleosome of H4. Also in this issue, Gottschling and coworkers formation, and highly charged, unstructured tail do(Parthun et al., 1996, this issue) describe the identificamains that protrude from the octamer. These tails are tion of a yeast histone acetyltransferase complex of important both for histone–DNA interactions and for inthe B type (HAT B, see below) likely to establish the teractions with other nonhistone proteins. Neutralization acetylation pattern associated with deposition of naof the positive charge associated with specific, often scent H4 into chromatin. Surprisingly, the yeast HAT B highly conserved, lysine residues within the histone tails complex and the human CAF-1 complex contain struc(see below and Figure 1) by acetylation provides a returally related 48 kDa subunits, providing a direct molversible mechanism for regulating these interactions. In ecular link between histone acetylation and chromatin the nucleus, all four histones are subject to acetylation, assembly. Moreover, human p48 has been isolated preand acetylation has long been proposed to ’loosen’ hisviously in association with a histone deacetylase (HD1) tone–DNA contacts within the nucleosome to facilitate (Taunton et al., 1996) and the Retinoblastoma (Rb) tumor binding of transacting, regulatory proteins to nucleososuppressor protein (Qian et al., 1995) and has therefore mal DNA. Acetylation also appears to play a critical role acquired the name RbAp48. Together these findings in influencing histone interactions with specific nonhisindicate that histone acetylation, deacetylation, and tone regulatory proteins (Brownell and Allis, 1996). chromatin assembly may be coordinated through comWhat governs the targeting and specificity of these mon p48 subunits, and that p48 or other factors involved interactions? The discovery that a yeast transcriptional in these processes may provide unique targets for the adaptor protein, Gcn5p, functions as the catalytic subregulation of cell proliferation. unit of a HAT A activity (Brownell et al., 1996) suggests Histone Acetylation: Who, Where, and Why? that HAT As are “recruited” to specific genes through The vast majority of histone synthesis is tightly coupled selective protein–protein interactions with a subset of to DNA replication in somatic cells, and newly synthetranscription factors. Perhaps HAT B’s are similarly tarsized histones are quickly recruited to replication forks geted to different cytosolic complexes and nuclear repliin the nucleus for assembly into chromatin. More than cation forks through interactions between the WD40 20 years ago, it was reported that nascent H3 and H4 domain (a known protein–protein interaction domain) in were post-translationally modified in thecytoplasm prior Hat2p and other proteins. Remarkably, the acetylation to their transport into the nucleus and assembly into site specificity of these two classes of enzymes, which chromatin, and that these modifications were removed both recognize the amino terminus of H4, is nonoverlapafter assembly (Ruiz-Carillo et al., 1975; Jackson et al., ping and is apparently generated by residues flanking