Academic journal article Genetics

Regulation of Histone Gene Expression in Budding Yeast

Academic journal article Genetics

Regulation of Histone Gene Expression in Budding Yeast

Article excerpt

ABSTRACT We discuss the regulation of the histone genes of the budding yeast Saccharomyces cerevisiae. These include genes encoding the major core histones (H3, H4, H2A, and H2B), histone H1 (HHO1), H2AZ (HTZ1), and centromeric H3 (CSE4). Histone production is regulated during the cell cycle because the cell must replicate both its DNA during S phase and its chromatin. Consequently, the histone genes are activated in late G1 to provide sufficient core histones to assemble the replicated genome into chromatin. The major core histone genes are subject to both positive and negative regulation. The primary control system is positive, mediated by the histone gene-specific transcription activator, Spt10, through the histone upstream activating sequences (UAS) elements, with help from the major G1/S-phase activators, SBF (Swi4 cell cycle box binding factor) and perhaps MBF (MluI cell cycle box binding factor). Spt10 binds specifically to the histone UAS elements and contains a putative histone acetyltransferase domain. The negative system involves negative regulatory elements in the histone promoters, the RSC chromatin-remodeling complex, various histone chaperones [the histone regulatory (HIR) complex, Asf1, and Rtt106], and putative sequence-specific factors. The SWI/SNF chromatin-remodeling complex links the positive and negative systems. We propose that the negative system is a damping system that modulates the amount of transcription activated by Spt10 and SBF. We hypothesize that the negative system mediates negative feedback on the histone genes by histone proteins through the level of saturation of histone chaperones with histone. Thus, the negative system could communicate the degree of nucleosome assembly during DNA replication and the need to shut down the activating system under replication-stress conditions. We also discuss post-transcriptional regulation and dosage compensation of the histone genes.

THE histone genes have been studied intensively for several decades in model organisms and in humans. Initially, they were studied because they encode proteins of major importance and their function in packaging DNA into the nucleus as chromatin was clearly understood and because they are excellent models for cell-cycle-dependent regulation of gene expression. However, the histone genes are atypical in that there are multiple copies of most histone genes in all organisms. In this regard, the yeasts are perhaps the most tractable model organisms. In particular, the budding yeast Saccharomyces cerevisiae possesses only two copies each of the major core histone genes. This review focuses on the regulation of the yeast histone genes.

The histones are highly positively charged proteins that package DNA, which is negatively charged, into the nucleus in the form of chromatin, the substance of chromosomes. Packaging was initially thought to be the only function of the histones, but it is now clear that they also participate in gene regulation via both classical and epigenetic mechanisms. Nevertheless, the regulatory mechanisms appear to act primarily by controlling the extent to which DNA is made accessible to regulatory factors, i.e., by controlling packaging.

The basic structural unit of chromatin is the nucleosome core, which is composed of two molecules each of the four core histones-H2A, H2B, H3, and H4-formed into an octamer, around which is wrapped 147 bp of DNA in 1.75 superhelical turns (Luger et al. 1997). The central 80 bp of the nucleosome is organized by an H3-H4 tetramer containing two molecules each of H3 and H4. H2A-H2B dimers are bound on both sides of the H3-H4 tetramer. More complex eukaryotes possess several variants of the histones H2A and H3. The only variants found in budding yeast are H2A.Z (a close variant of H2A) and CenH3 (an H3 variant found only in centromeric nucleosomes). The nucleosome is the structural repeat unit of chromatin and includes the linker DNA and the linker histone H1 (Thoma et al. …

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