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. 2000 Dec 5;97(25):13708-13.
doi: 10.1073/pnas.250477697.

Genomewide studies of histone deacetylase function in yeast

B E Bernstein  1 , J K Tong, S L Schreiber
Affiliations

Genomewide studies of histone deacetylase function in yeast

B E Bernstein et al. Proc Natl Acad Sci U S A. .

Erratum in

  • Proc Natl Acad Sci U S A 2001 Apr 24;98(9):5368

Abstract

The trichostatin A (TSA)-sensitive histone deacetylase (HDAC) Rpd3p exists in a complex with Sin3p and Sap30p in yeast that is recruited to target promoters by transcription factors including Ume6p. Sir2p is a TSA-resistant HDAC that mediates yeast silencing. The transcription profile of rpd3 is similar to the profiles of sin3, sap30, ume6, and TSA-treated wild-type yeast. A Ume6p-binding site was identified in the promoters of genes up-regulated in the sin3 strain. Two genes appear to participate in feedback loops that modulate HDAC activity: ZRT1 encodes a zinc transporter and is repressed by RPD3 (Rpd3p is zinc-dependent); BNA1 encodes a nicotinamide adenine dinucleotide (NAD)-biosynthesis enzyme and is repressed by SIR2 (Sir2p is NAD-dependent). Although HDACs are transcriptional repressors, deletion of RPD3 down-regulates certain genes. Many of these are down-regulated rapidly by TSA, indicating that Rpd3p may also activate transcription. Deletion of RPD3 previously has been shown to repress ("silence") reporter genes inserted near telomeres. The profiles demonstrate that 40% of endogenous genes located within 20 kb of telomeres are down-regulated by RPD3 deletion. Rpd3p appears to activate telomeric genes sensitive to histone depletion indirectly by repressing transcription of histone genes. Rpd3p also appears to activate telomeric genes repressed by the silent information regulator (SIR) proteins directly, possibly by deacetylating lysine 12 of histone H4. Finally, bioinformatic analyses indicate that the yeast HDACs RPD3, SIR2, and HDA1 play distinct roles in regulating genes involved in cell cycle progression, amino acid biosynthesis, and carbohydrate transport and utilization, respectively.

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Figures

Figure 1
Figure 1
The rpd3 and sin3 profiles are highly similar. (A) Venn diagrams comparing sets of up- and down-regulated genes from the rpd3 and sin3 data sets. (B) Plot of sin3-derived ratios vs. rpd3-derived expression ratios for each gene. A correlation of 0.85 is observed between the two data sets. (C) Transcripts previously identified as up-regulated in rpd3 or sin3 are also observed to be up-regulated in the microarray data.
Figure 2
Figure 2
Transcription profiles support a model of HDAC function. (A) A common regulatory sequence, GGCGGCNAN, was found between 10 and 500 bp upstream of the translation start site for a subset of genes up-regulated in sin3. This sequence corresponds to the known regulatory sequence URS1, which is bound by Ume6p, a protein that recruits the Sin3p-Rpd3p corepressor complex (7). (B) Lists of genes up-regulated in the rpd3 and sin3 profiles are similar to lists of genes up-regulated in the sap30, ume6, and TSA data sets. This is consistent with the molecular model for Rpd3p function depicted in C.
Figure 3
Figure 3
Feedback inhibition modulates HDAC activity. Two genes were identified as potential modulators of RPD3- and SIR2-mediated repression: the zinc transporter gene, ZRT1, is repressed by the zinc-dependent HDAC, Rpd3p; the NAD-biosynthesis gene, BNA1, is repressed by the NAD-dependent HDAC, Sir2p (12) (B.E.B. and S.L.S., unpublished results). Interestingly, RPD3 activates BNA1, and SIR2 appears to activate ZRT1. The particular acetylation pattern induced by these HDACs may, in certain cases, activate transcription (see text and Fig. 5). Fold changes induced by RPD3 deletion, SIR2 deletion, and by 15 min and 30 min TSA treatments are shown.
Figure 4
Figure 4
Chromosomal view of RPD3-regulated genes. RPD3 deletion results in the 2-fold up-regulation of 170 genes (depicted in red) and the 2-fold down-regulation of 264 genes (depicted in green). One hundred of the down-regulated genes are located within 20 kb of telomeric ends.
Figure 5
Figure 5
RPD3 disruption represses genes near telomeric ends. (A) RPD3 deletion and histone H4 depletion both regulate genes within 15–20 kb of telomere ends. In contrast, SIR2 deletion regulates genes within 5–10 kb of these ends (13). (B) Like RPD3 deletion, TSA treatment down-regulates telomeric genes. Telomeric genes sensitive to SIR deletion (12) are repressed rapidly by TSA. Telomeric genes sensitive to H4 depletion (13) are slowly repressed by TSA. Like RPD3 deletion, TSA up-regulates histone genes. Taken together, these data support a model in which RPD3 abrogates telomeric silencing via the direct and indirect mechanisms outlined in C. (C) Rpd3p appears to activate telomeric genes directly by deacetylating histone H4 lysine 12 and, thereby, hindering repression by SIR proteins. Rpd3p appears to activate telomeric genes indirectly by repressing histone genes.
Figure 6
Figure 6
RPD3, HDA1, and SIR2 influence distinct functional classes. Lists of genes up-regulated at least 1.5-fold in the rpd3, hda1, and sir2 (12) profiles are compared in a Venn diagram. Bioinformatic analysis suggests that RPD3 influences cell cycle progression, HDA1 influences carbon metabolite and carbohydrate transport and utilization, and SIR2 influences amino acid biosynthesis. The number of genes in the functional class regulated by the deletion/total number of genes in the functional class are shown in parentheses.
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