Histone Acetylation at Promoters Is Differentially Affected by Specific Activators and Repressors

Abstract

We analyzed the relationship between histone acetylation and transcriptional regulation at 40 Saccharomyces cerevisiae promoters that respond to specific activators and repressors. In accord with the general correlation between histone acetylation and transcriptional activity, Gcn4 and the general stress activators (Msn2 and Msn4) cause increased acetylation of histones H3 and H4. Surprisingly, Gal4-dependent activation is associated with a dramatic decrease in histone H4 acetylation, whereas acetylation of histone H3 is unaffected. A specific decrease in H4 acetylation is also observed, to a lesser extent, at promoters activated by Hap4, Adr1, Met4, and Ace1. Activation by heat shock factor has multiple effects; H4 acetylation increases at some promoters, whereas other promoters show an apparent decrease in H3 and H4 acetylation that probably reflects nucleosome loss or gross alteration of chromatin structure. Repression by targeted recruitment of the Sin3-Rpd3 histone deacetylase is associated with decreased H3 and H4 acetylation, whereas repression by Cyc8-Tup1 is associated with decreased H3 acetylation but variable effects on H4 acetylation; this suggests that Cyc8-Tup1 uses multiple mechanisms to reduce histone acetylation at promoters. Thus, individual activators confer distinct patterns of histone acetylation on target promoters, and transcriptional activation is not necessarily associated with increased acetylation. We speculate that the activator-specific decrease in histone H4 acetylation is due to blocking the access or function of an H4-specific histone acetylase such as Esa1.

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

“…This H3 deacetylation cannot be explained by TSA degradation or efflux as global hyperacetylation remains high at the whole nucleus level. This decrease in acetylated H3 might be linked to nucleosomes loss instead of H3 deacetylation (Deckert and Struhl, 2001), but this seems rather unlikely as this loss would result in concomitant decrease in acetylated H4 level. H4 by TSA has already been described at the level of mouse mammary tumour virus and c-jun promoters (Thompson et al, 2001;Mulholland et al, 2003), and even ABCB1 promoter in CEMBcl2 cells (Baker et al, 2005).…”

Src family kinase members have a common response to histone deacetylase inhibitors in human colon cancer cells

“…Deacetylation of histones (especially H4) associated with the promoter region is a frequent observation in yeast and human genes following transcriptional activation. 53,54 The growing list of nonhistone proteins regulated by acetylation/deacetylation, which includes some 301 transcription factors, further complicates this issue. 55 HDIs appear to act though a distinct reprogramming of gene expression, which activates genes involved in cell cycle arrest such as p21 WAF1 while repressing genes involved in proliferation such as cyclin D1 and c-Myc.…”

Splitting of H3–H4 tetramers at transcriptionally active genes undergoing dynamic histone exchange

“…Recruitment is mediated either by activator proteins bound at promoter regions (17)(18)(19)(20)(21) or by elongating Pol II (and associated factors) at highly transcribed genes (21-24). We presume that the nucleosome-remodeling complexes and/or histone chaperones responsible for rapid histone exchange differ from those used during DNA replication.…”