HAT-HDAC interplay modulates global histone H3K14 acetylation in gene-coding regions during stress - PubMed (original) (raw)

HAT-HDAC interplay modulates global histone H3K14 acetylation in gene-coding regions during stress

Anna Johnsson et al. EMBO Rep. 2009 Sep.

Abstract

Histone acetylation and deacetylation are important for gene regulation. The histone acetyltransferase, Gcn5, is an activator of transcriptional initiation that is recruited to gene promoters. Here, we map genome-wide Gcn5 occupancy and histone H3K14ac at high resolution. Gcn5 is predominantly localized to coding regions of highly transcribed genes, where it collaborates antagonistically with the class-II histone deacetylase, Clr3, to modulate H3K14ac levels and transcriptional elongation. An interplay between Gcn5 and Clr3 is crucial for the regulation of many stress-response genes. Our findings suggest a new role for Gcn5 during transcriptional elongation, in addition to its known role in transcriptional initiation.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1

Figure 1

Gcn5 is located in the coding region of highly transcribed genes. (A) High-resolution tiling arrays show the enrichment of Gcn5–Myc (blue trace) in the ORFs (black boxes) of many genes within a representative region of chromosome II. (B) Average gene analysis shows that Gcn5–Myc is preferentially enriched in the coding regions of highly expressed genes. Genes are grouped according to their expression level (n indicates the number of genes in each subclass). (C) Cell-plating assay showing that _gcn5_Δ is sensitive to MPA (50 μl/ml), in a manner similar to the deletion of elongation factor TFIIS. The control plate shows growth on PMG. (D) Gcn5–Myc occupancy correlates with the occupancy of several HDACs and histone marks. The table shows significant overlaps between Gcn5-bound ORFs (_n_=835, twofold enrichment) and groups of ORFs bound by various HDACs or containing different HDAC-dependent chromatin modifications (normalized for H3 occupancy). The _P_-value indicates the significance associated with the hypogeometrical distribution test. HDAC, histone deacetylase; IGR, intergenic region; MPA, mycophenolic acid; ORF, open reading frame; PMG, pombe glutamate medium; wt, wild type.

Figure 2

Figure 2

Genetic interaction between Gcn5 and the class-II histone deacetylase Clr3 links the stress response to acetylation of histone H3K14. Cell-plating assay showing that (A) _clr3_Δ specifically rescues growth of the _gcn5_Δ mutant on 1 M KCl and heat (36°C), and (B) that mutation of histone H3 that mimics hypoacetylation of lysine 14 (H3K14R) is uniquely sensitive to 1 M KCl. Growth on rich medium (YES) at 25°C is shown (control). wt, wild type; YES, yeast extract with supplements.

Figure 3

Figure 3

Gcn5 and Clr3 have opposing effects on global histone H3K14 acetylation in gene coding regions. (A) High-resolution tiling arrays showing occupancy of H3K14ac (corrected for nucleosome density) and histone H3 in wild-type, _gcn5_Δ and _gcn5_Δ_clr3_Δ strains. A representative region of chromosome III is shown. (B,C) Average gene analysis of H3K14ac levels in wild-type, _gcn5_Δ and _gcn5_Δ_clr3_Δ strains, (B) before and (C) after correction for nucleosome density. Genes were divided into subclasses with various expression levels as in Fig 1B. IGR, intergenic region; WT, wild type.

Figure 4

Figure 4

Deletion of clr3 suppresses the elongation phenotype and restores the expression of genes affected by the deletion of gcn5. (A) Cell-plating assay showing suppression of MPA sensitivity in _gcn5_Δ by deletion of _clr3_+ but not sir2+. Data for wild type, _TFIIS_Δ and _gcn5_Δ (upper panel) and annotations are as in Fig 1C. (B) Scatter plot showing that genes with decreased expression in _gcn5_Δ compared with wild type had increased expression in _gcn5_Δ_clr3_Δ compared with _gcn5_Δ, and vice versa, during KCl-induced stress. Expression ratios of the 216 genes shown were significantly altered in both data sets (P<0.05). MPA, mycophenolic acid; wt, wild type.

References

    1. Baker SP, Grant PA (2007) The SAGA continues: expanding the cellular role of a transcriptional co-activator complex. Oncogene 26: 5329–5340 - PMC - PubMed
    1. Bjerling P, Silverstein RA, Thon G, Caudy A, Grewal S, Ekwall K (2002) Functional divergence between histone deacetylases in fission yeast by distinct cellular localization and in vivo specificity. Mol Cell Biol 22: 2170–2181 - PMC - PubMed
    1. Durand-Dubief M, Sinha I, Fagerstrom-Billai F, Bonilla C, Wright A, Grunstein M, Ekwall K (2007) Specific functions for the fission yeast Sirtuins Hst2 and Hst4 in gene regulation and retrotransposon silencing. EMBO J 26: 2477–2488 - PMC - PubMed
    1. Ekwall K (2005) Genome-wide analysis of HDAC function. Trends Genet 21: 608–615 - PubMed
    1. Govind CK, Zhang F, Qiu H, Hofmeyer K, Hinnebusch AG (2007) Gcn5 promotes acetylation, eviction, and methylation of nucleosomes in transcribed coding regions. Mol Cell 25: 31–42 - PubMed

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