Steps toward understanding the inheritance of repressive methyl-lysine marks in histones.

organisms proceeds according to a pattern of gene expression that is adjusted temporally and spatially. It has become evident that changes within the chromatin structure brought about by covalent modifications of histones are of crucial importance in this as well as in many other biological processes. A focus of our studies involves the identity and functional roles of the cellular proteins that enable the transcriptional machinery to access and move through the nucleosomal DNA. This entails alterations within the nucleosomal structure. To get to this stage, the overall chromatin structure must unfold. Our recent studies have focused on the properties of the nucleosomal proteins that are determinant to the overall organization of compacted chromatin. It is these proteins that proscribe or enable DNA accessibility. The complex chromosome structure around silent genes is tightly wound (heterochromatin) prohibiting access to the transcriptional machinery, while it is more loosely wrapped around the genes active in RNA synthesis (euchromatin). Over the past few years, researchers have uncovered that the key to these two different chromatin structures resides in the histone tails that embody unstructured, hooklike projections extending outward from each nucleosome. Posttranslational modifications in these histone tails determine whether they lock together tightly or loosely and thus whether the genes spooled around them are silent or active. Several discoveries in 1996 heralded a momentous year for members of the transcription and chromatin communities. Two reports provided the long awaited connection between chromatin and the regulation of gene expression. In one report, Allis and coworkers (Brownell et al. 1996) described a histone acetyltransferase and discovered that it was GCN5, whose gene was previously identified in yeast using a genetic screen scoring for transcriptional regulators. In a second report, Schreiber and coworkers (Taunton et al. 1996) uncovered that a histone deacetylase resides in a mammalian homolog of yeast RPD3, originally isolated in genetic screens scoring for transcriptional repressors. These were groundbreaking discoveries. Subsequent developments enhanced their impact by showing that the enzymatic activities of Gcn5 and Rpd3 are regulated through their association with other proteins (Sterner and Berger 2000; Kuzmichev and Reinberg 2001). These findings galvanized the field of chromatin research, within the context of transcriptional regulation and gene expression. We now know that many regulators of transcription contain activities that covalently modify the histone tails (Struhl 1998; Sterner and Berger 2000). Another important finding that intersected histone methylation with heterochromatin formation came about 4 years later. Jenuwein and colleagues (Rea et al. 2000) uncovered that the mammalian homolog of a gene initially isolated in Drosophila as a suppressor of variegation, Suv39H1, and its Schizosaccharomyces pombe homolog, CLR4, encode proteins with intrinsic histone lysine methyltransferase (HKMT) activity. These respective HKMT activities exhibited a strict specificity for lysine-9 of histone H3, a residue previously identified as being methylated in vivo (DeLange et al. 1973). Lysine residues can potentially be fully methylated generating trimethylated moieties; however, HKMTs can incorporate mono-, di-, or trimethyl groups (Zhang and Reinberg 2001), providing another level of diversity in regulation. The bond formed between the side chain of lysine and the methyl group is not easily reversed (Bannister et al. 2002; Kubicek and Jenuwein 2004). The stability of this lysinemethyl bond is a unique property of this modification. Similar to clusters of CpG methylation in DNA, histone lysine methylations are now appreciated as stably modified chromatin constituents whose transfer from mother to daughter cells qualifies the epigenetic process. Thus, histone lysine methylations are categorized as “epigenetic marks” (Jenuwein and Allis 2001; Sims et al. 2003). Importantly, numerous studies have provided evidences that the enzymes responsible for the modifications of histones function in a coordinated pattern to control gene expression (Berger 2002; Ng et al. 2002; Sun and Allis Steps Toward Understanding the Inheritance of Repressive Methyl-Lysine Marks in Histones