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Review
. 2012 May;191(1):7-20.
doi: 10.1534/genetics.112.140145.

Regulation of histone gene expression in budding yeast

Peter R Eriksson  1 , Dwaipayan Ganguli, V Nagarajavel, David J Clark
Affiliations
Review

Regulation of histone gene expression in budding yeast

Peter R Eriksson et al. Genetics. 2012 May.

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.

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Figures

Figure 1
Figure 1
The yeast histone genes. (A) Organization of the histone genes. The histone UAS elements are shown as numbered open arrowheads, which indicate their orientation. Confirmed high-affinity binding sites for Swi4 (SBF) are shown as blue boxes with arrowheads to indicate orientation; additional low-affinity sites exist but are not shown. An exact match to the Mbp1 consensus (ACGCGT) is indicated as a green box; there might be other high-affinity sites that differ from the consensus. The NEG region in HTA1-HTB1 is indicated by a red bar. Putative NEG elements are indicated by red boxes and the CCR′ element by an orange box. (B) Sequences of the functional histone UAS elements (nucleotides in red form the Spt10-binding site) (adapted from Eriksson et al. 2005). (C) Sequences of confirmed high-affinity Swi4 sites. (D) Sequence motif for the NEG element (from Mariño-Ramirez et al. 2006).
Figure 2
Figure 2
Structure of the histone gene activator, Spt10. (A) Domain structure of Spt10: NTD, N-terminal domain; HAT, histone acetyltransferase domain; DBD, DNA-binding domain; C1 and C2, arbitrarily defined C-terminal domains. (B) Model for cooperative binding of the Spt10 dimer to a pair of histone UAS elements. The NTD-HAT-DBD portion of Spt10 forms a relatively compact dimer stabilized through interactions between its N-terminal domains (N). The C1 and C2 domains have been omitted for clarity. It is proposed that the DNA-binding domains, D, are oriented such that the DNA-binding site (black crescents) cannot interact fully with a single UAS element. However, if two such elements are present, the combined interactions of each DBD with part of a UAS are sufficient to trigger a conformational change in Spt10, resulting in high-affinity binding. The DBD alone can bind with high affinity to a single UAS. Adapted from Mendiratta et al. (2007).
Figure 3
Figure 3
Contributions of Spt10, SBF, and the UAS elements to the activation of HTA1-HTB1 (idealized). Cells were arrested with α-factor and released. (Top) The total HTA1/HTB1 mRNA peak (black) is composed of two peaks: a small, Swi4-dependent early peak (green) and a later major peak dependent on Spt10 (blue). Also shown is the effect of mutations on the UAS elements (purple). (Bottom) Binding of Spt10 and Swi4 at the HTA1-HTB1 promoter, as shown by ChIP. Adapted from Eriksson et al. (2011).
Figure 4
Figure 4
Cell-cycle-dependent binding of the RSC and SWI/SNF ATP-dependent chromatin-remodeling complexes at the HTA1-HTB1 promoter. The binding of TFIIB, a general transcription factor present at active promoters, coincides with that of SWI/SNF, but is out of phase with that of RSC. Thus, SWI/SNF binding correlates with activation, and RSC binding correlates with repression. ChIP data for TFIIB and RSC were adapted from Ng et al. (2002); data for SWI/SNF and HTA1 expression were adapted from Ferreira et al. (2011). Note that, although these experiments were done in two different laboratories, the times between the first and second cell-cycle peaks are very similar, and so a direct comparison is reasonable.
Figure 5
Figure 5
Model for the activated and repressed states of the HTA1-HTB1 promoter. In late G1 and S phase, the histone genes are transcriptionally active. Activation occurs through SBF and Spt10 binding at the UAS elements (open triangles). Activation proceeds through an unknown mechanism involving the SWI/SNF-remodeling complex, the binding of which is dependent on the NEG region (red box) and perhaps on a putative sequence-specific NEG transcription factor (red circle). The promoter is shown depleted of nucleosomes (gray ovals), perhaps due to SWI/SNF, but direct evidence for this chromatin structure is lacking. Note that there is likely to be some nucleosome formation on the promoter because there is an enrichment for acetylated H3-K56. Cell-cycle kinases might be involved in activating Spt10; its HAT domain is required for its activation function. Outside S phase, Spt10 and SBF are no longer bound; whether they are displaced or degraded is not known. Establishment of the repressed state depends on histone chaperones (HIR, Rtt106, and Asf1), the putative NEG factor, and the RSC remodeling complex, which are proposed to facilitate nucleosome assembly on the promoter.
Figure 6
Figure 6
Hypothesis: Negative feedback by histones links the positive and negative regulatory systems. The histone genes are activated by Spt10 and SBF bound to the histone UAS elements (open triangles), followed by transcription and translation to produce histones. The NEG system inhibits activation through a putative sequence-specific NEG factor (open red circle) bound to the NEG region (red box), which recruits various histone chaperones (HIR, Rtt106, and Asf1: red oval). Inhibition occurs only if histones are bound to the chaperones. The chaperones will be fully charged with histone and maximally inhibitory when there is no replicated DNA available in the cell for nucleosome assembly—when replication is complete (outside S phase) or if replication forks are stalled (e.g., in the presence of hydroxyurea). Outside S phase, the activators are displaced or degraded (arrows). Our hypothesis is based particularly on our own work and that of Moran et al. (1990) and Fillingham et al. (2009). There are additional levels of control at the levels of mRNA stability and Rad53-mediated histone degradation (not shown).
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