Silencers, silencing, and heritable transcriptional states

Abstract

Three copies of the mating-type genes, which determine cell type, are found in the budding yeast Saccharomyces cerevisiae. The copy at the MAT locus is transcriptionally active, whereas identical copies of the mating-type genes at the HML and HMR loci are transcriptionally silent. Hence, HML and HMR, also known as the silent mating-type loci, are subject to a position effect. Regulatory sequences flank the silent mating-type loci and mediate repression of HML and HMR. These regulatory sequences are called silencers for their ability to repress the transcription of nearby genes in a distance- and orientation-independent fashion. In addition, a number of proteins, including the four SIR proteins, histone H4, and an alpha-acetyltransferase, are required for the complete repression of HML and HMR. Because alterations in the amino-terminal domain of histone H4 result in the derepression of the silent mating-type loci, the mechanism of repression may involve the assembly of a specific chromatin structure. A number of additional clues permit insight into the nature of repression at HML and HMR. First, an S phase event is required for the establishment of repression. Second, at least one gene appears to play a role in the establishment mechanism yet is not essential for the stable propagation of repression through many rounds of cell division. Third, certain aspects of repression are linked to aspects of replication. The silent mating-type loci share many similarities with heterochromatin. Furthermore, regions of S. cerevisiae chromosomes, such as telomeres, which are known to be heterochromatic in other organisms, require a subset of SIR proteins for repression. Further analysis of the transcriptional repression at the silent mating-type loci may lend insight into heritable repression in other eukaryotes.

The carboxy termini of Sir4 and Rap1 affect Sir3 localization: evidence for a multicomponent complex required for yeast telomeric silencing.

“…Repression of the silent mating type loci in yeast and the related phenomenon of telomere-mediated gene silencing provide two of the best characterized examples of chromatin structure affecting gene expression. As discussed above, genetic and biochemical studies implicate the products of the RAP1 and the SIR2-4 genes in both instances of transcrip-tional repression (for review see Laurenson and Rine, 1992). Although RAP1 appears to exert its influence by binding directly to its consensus sites, there is no evidence that any of the SIR gene products bind DNA directly.…”

“…HE regulation of gene expression by alterations in chromatin structure is a universal phenomenon in eukaryotic cells, and is responsible for the proper activation and inactivation of genes in the developmental program of multicellular organisms (Paro, 1993;Tartof and Bremer, 1990), for position effect variegation in flies (Eissenberg, 1989;Henikoff, 1990), and the variable expression of foreign genes integrated into chromosomes (e.g., Butner and Lo, 1986). In the yeast Saccharomyces cerevisiae, gene repression at the silent mating type loci (HML and HMR, collectively termed the HM loci) appears to involve a reduction in the accessibility of the entire domain to the transcription machinery, the yeast endonuclease HO, and to other modifying enzymes (for review see Laurenson and Rine, 1992). Similarly, the transcription of Pol II genes positioned adjacent to the poly(TGt.3) tracts at yeast telomeres was found to be metastable, switching between repressed and derepressed states in a process called telomeric position effect or silencing (Gottschling et al, 1990).…”

“…The effects of mutations in RAP/and SIR genes implicate these gene products directly in the repression mechanism, possibly through physical interactions among these proteins (for review see Laurenson and Rine, 1992;Palladino and Gasser, 1994). For instance, deletions of 28 aa or more from the COOH terminus of RAP1 abrogate telomeric silencing (Kyrion et al, 1992;Liu et al, 1994).…”

Chromosomal Inheritance of Epigenetic States in Fission Yeast During Mitosis and Meiosis

“…To gain an insight into the role of K-sequences in silenctranscriptional repression at silent donor loci (reviewed ing in this region, we replaced 7.5 kb of the K-region by Laurenson and Rine, 1992;Klar, 1992), near telo-(see Figure 1) with the ura4 marker gene to generate an meres (Gottschling et al, 1990;Nimmo et al, 1994) and h 90 , K⌬ ::ura4 strain (SPG27; see Table 1 for complete centromeres (Allshire et al, 1994(Allshire et al, , 1995 closely parallel genotype; Figure 1). Two results showed that the donor position-effect control observed in higher eukaryotes.…”

PCNA Loaders and Unloaders—One Ring That Rules Them All

“…In S. cerevisiae, the two primary histone post-translational modifications that control the epigenetic state are the acetylation and methylation of histone H4 or H3 [143,144]. Histone acetyltransferases (HATs) acetylate histones and make the chromatin more accessible, and histone deacetylases (HDACs) promote heterochromatin formation [145,146].…”