Yeast heterochromatin: regulation of its assembly and inheritance by histones.

Ekwall et al. 1997xEkwall, K, Olsson, T, Turner, B.M, Cranston, G, and Allshire, R.C. Cell. 1997; 91: 1021–1032Abstract | Full Text | Full Text PDF | PubMed | Scopus (288)See all ReferencesEkwall et al. 1997 have recently reported a surprising finding that also implicates histone acetylation in the propagation of chromosomal structures during cell division. They found that treating S. pombe for five cell doublings with the histone deacetylase inhibitor trichostatin A (TSA) causes centromeric heterochromatin to become hyperacetylated. Instead of the heterochromatin-specific pattern (here too, H4 acetylation mainly at K12), sites K5, K8, and K16 were more strongly acetylated. This was correlated with derepression of reporter genes at centromeric heterochromatin and defects in chromosomal segregation. Moreover, derepression of the marker genes was tightly linked to the centromeric region (cen1) itself, arguing that derepression is not due to the effect of TSA on a chromosomal gene in euchromatin whose derepression could act in trans on cen1. Surprisingly, the hyperacetylated state and the defects in repression and segregation were maintained even 80–100 generations after TSA was removed (Ekwall et al. 1997xEkwall, K, Olsson, T, Turner, B.M, Cranston, G, and Allshire, R.C. Cell. 1997; 91: 1021–1032Abstract | Full Text | Full Text PDF | PubMed | Scopus (288)See all ReferencesEkwall et al. 1997). Perhaps, the hyperacetylated state prevents heterochromatin formation, thereby increasing access to histone acetyltransferases. This may ensure a decondensed state that may be acetylated and propagated as such in subsequent generations.Therefore, as in S. cerevisiae telomeric heterochromatin, the acetylation state of H4 may serve as a platform for the assembly of S. pombe centromeric factors—in particular, those required for repression and segregation. Moreover, the acetylation state resulting from TSA treatment may provide a chromosomal imprint that serves as a template for its inheritance in subsequent generations. This has profound implications for the inheritance of the normal hypoacetylated state of heterochromatin (telomeric or centromeric). It suggests that the H4 acetylation state is a template for its propagation during cell division (Figure 3Figure 3). This may occur if the heterochromatin-specific state is recognized by histone deacetylases (or deacetylases and acetyltransferases) that duplicate this state on newly assembled histones during heterochromatin replication. Alternatively, some other aspect of the heterochromatin-specific structural state, perhaps the assembled SIR proteins, may be recognized. It is also possible that templating of the acetylation state from old to new nucleosomes involves the CAF1 complex. This could occur if the complex recognizes some aspect of mature heterochromatin and can then transfer appropriately acetylated H4 to new nucleosomes. In either case, once assembled, the SIR complex may prevent access to enzymes that promote further cycles of acetylation and deacetylation, thus protecting the heterochromatin-specific acetylation pattern. The inheritance of a particular acetylated state may also explain epigenetic inheritance. If the balance shifts to hypoacetylation in some cells, this would allow subsequent inheritance of the repressed state of heterochromatin; shifting the balance to hyperacetylation would propagate the active state.Figure 3The Heterochromatin-Specific Hypoacetylated State in which H4 Lysine K12 Is Uniquely Acetylated May Serve as a Blueprint for Its PropagationThis could occur if histone deacetylases (HDs) or even a combination of deacetylases and acetyltransferases recognize the acetylated state or any other structural feature of mature heterochromatin on old nucleosomes (blue) and transfer this acetylated state to new nucleosomes (yellow). It is also possible that CAF1 components recognize mature heterochromatin and transfer H4 acetylated at K12 to new nucleosomes. The heterochromatin-specific hypoacetylated state may then serve as a platform for heterochromatin protein assembly.View Large Image | View Hi-Res Image | Download PowerPoint SlideIn conclusion, recent observations have pointed to new and surprising functions for histones and histone acetylation in regulating heterochromatin structure and its inheritance. Histone acetylation has long been thought to affect histone–DNA interactions. While this may still be true, there are cases where it may regulate protein–protein interactions that determine heterochromatin initiation and which allow heterochromatin to spread. In addition, acetylation may differentially regulate histone–histone internucleosomal interactions in heterochromatin and euchromatin. This has important physiological considerations. Heterochromatin is implicated in numerous functions, including the protection of chromosomal ends, genetic repression, chromosomal segregation, telomere length regulation, and even cellular senescence (Lowell and Pillus 1998xLowell, J.E and Pillus, L. Cell. Mol. Life Sci., in press. 1998; See all ReferencesLowell and Pillus 1998). Since certain of the factors involved in yeast heterochromatin (e.g., RAP1, SIR2, histones) are strongly conserved or have homologs in higher cells, including humans, the study of yeast heterochromatin should be applicable to understanding its many important functions in all eukaryotes.