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. 1996;5(4-5):245-53.

The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation

C Van Lint  1 , S Emiliani, E Verdin
Affiliations

The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation

C Van Lint et al. Gene Expr. 1996.

Abstract

Posttranslational modifications of histones in chromatin are emerging as an important mechanism in the regulation of gene expression. Changes in histone acetylation levels occur during many nuclear processes such as replication, transcriptional silencing, and activation. Histone acetylation levels represent the result of a dynamic equilibrium between competing histone deacetylase(s) and histone acetylase(s). We have used two new specific inhibitors of histone deacetylase, trichostatin A (TSA) and trapoxin (TPX), to probe the effect of histone hyperacetylation on gene expression. We confirm that both drugs block histone deacetylase activity and have no detectable effects on histone acetylation rates in human lymphoid cell lines. Treatment with either TSA or TPX results in the transcriptional activation of HIV-1 gene expression in latently infected cell lines. In contrast, TSA and TPX cause a rapid decrease in c-myc gene expression and no change in the expression of the gene for glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Using differential display to compare the differences in gene expression between untreated cells and cells treated with TSA, we found that the expression of approximately 2% of cellular genes (8 genes out of approximately 340 examined) changes in response to TSA treatment. These results demonstrate that the transcriptional regulation of a restricted set of cellular genes is uniquely sensitive to the degree of histone acetylation in chromatin.

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Figures

FIG. 1
FIG. 1
TSA and TPX inhibit histone deacetylation in lymphoid cell lines. (A) Histones were acid extracted from Jurkat or SupT1 cells treated with TSA (400 nM) or TPX (10 nM) for 0, 2, or 16 h and separated on a 15% Triton-acid-urea gel. Histones were visualized after silver staining and the portion of the gel corresponding to different acetylated isoforms of histone H4 is shown. (B, C) Jurkat cells were pulsed for 30 min with [3H]acetate (250 μCi/ml NEN), washed, and chased for 0–4 h in the presence of TNF-α (80 U/ml) or TSA (400 nM). Nuclei were either acid extracted and the purified histones loaded on a 12% polyacrylamide denaturing gel (B) or directly resuspended in Laemmli buffer and loaded on a 12% polyacrylamide denaturing gel to examine all nuclear proteins (C). Molecular weight markers in kDa are indicated on the left of the gel. The position of different histones is indicated on the right.
FIG. 2
FIG. 2
Induction of HIV-1 expression in J49 cells by TSA and TPX. (A) J49 cells were incubated in the presence of different concentrations of both TPX and TSA as indicated and RNA was harvested at 8 h posttreatment. TNF-α was used at 800 U/ml. (B) TPX (100 nM) or TSA (400 nM) was added to J49 cells, for 0–32 h. Harvested RNA were analyzed by RNase protection analysis using an HIV-1 LTR-specific antisense probe (23) and a GAPDH antisense probe. The HIV-1 probe protects two fragments corresponding to the 5′ and 3′ LTR and only the 5′ LTR protected band is shown.
FIG. 3
FIG. 3
TPX and TSA suppresses c-myc gene expression. ACH2 cells were treated for different periods of time (0–32 h) with TSA (400 nM), TPX (100 nM), or TNF-α (800 U/ml). RNase protection analysis was performed using specific anti-sense probes for c-myc, GAPDH, and the HIV-1 LTR (23).
FIG. 4
FIG. 4
Differential display analysis of Jurkat, SupT1 mRNA in response to TSA. Total RNA from Jurkat and SupT1 cells was analyzed by differential display and the amplified products separated on sequencing gels. Regions from the gels containing mRNAs whose expression is modulated by TSA are shown. cDNAs whose expression is modulated in response to TSA are indicated by an arrow. (A) Jurkat RNA amplified with primers AP4 and C, (B) Jurkat with primers AP2 and A, (C) SupT1 RNA with primers API and G, (D) Jurkat RNA with primers AP5 and A, and (E) SupT1 RNA with primers AP5 and G.
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