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Genes are often sheltered from the global histone hyperacetylation induced by HDAC inhibitors.

Halsall J, Gupta V, O'Neill LP, Turner BM, Nightingale KP - PLoS ONE (2012)

Bottom Line: Different gene populations respond to each inhibitor, with as many genes down- as up-regulated.Surprisingly, HDACi rarely induced increased histone acetylation at gene promoters, with most genes examined showing minimal change, irrespective of whether genes were up- or down-regulated.Many genes seem to be sheltered from the global histone hyperacetyation induced by HDACi.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

ABSTRACT
Histone deacetylase inhibitors (HDACi) are increasingly used as therapeutic agents, but the mechanisms by which they alter cell behaviour remain unclear. Here we use microarray expression analysis to show that only a small proportion of genes (∼9%) have altered transcript levels after treating HL60 cells with different HDACi (valproic acid, Trichostatin A, suberoylanilide hydroxamic acid). Different gene populations respond to each inhibitor, with as many genes down- as up-regulated. Surprisingly, HDACi rarely induced increased histone acetylation at gene promoters, with most genes examined showing minimal change, irrespective of whether genes were up- or down-regulated. Many genes seem to be sheltered from the global histone hyperacetyation induced by HDACi.

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Histone acetylation changes on up- and down-regulated genes during extended VPA treatment.Chromatin-immunoprecipitation analysis of H4K8ac on: (A), Up-regulated gene (DLK1), (B), Down-regulated genes (LMO2, MYC) or (C), repetitive elements (ALU) in response to VPA treatment (5 mM). Analysis was performed on either untreated cells (Control), or during VPA treatment (15, 60 & 240minutes). Primer locations are indicated on the gene diagrams. The abundance of a histone modification (‘Enrichment’) is calculated from the ratio of material detected in bound∶unbound fractions.
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pone-0033453-g005: Histone acetylation changes on up- and down-regulated genes during extended VPA treatment.Chromatin-immunoprecipitation analysis of H4K8ac on: (A), Up-regulated gene (DLK1), (B), Down-regulated genes (LMO2, MYC) or (C), repetitive elements (ALU) in response to VPA treatment (5 mM). Analysis was performed on either untreated cells (Control), or during VPA treatment (15, 60 & 240minutes). Primer locations are indicated on the gene diagrams. The abundance of a histone modification (‘Enrichment’) is calculated from the ratio of material detected in bound∶unbound fractions.

Mentions: Finally, we extended this experiment to analyse three classes of genes – (i) a gene those that showed early and progressive up-regulation (DLK1,Fig. 5A), (ii) genes that show down-regulation (LMO2, MYC,Fig. 5B), and (iii) an abundant repetitive element, ALU (Yb8) (Fig. 5C). In all cases H4K8ac abundance was low at promoter-proximal loci (i.e. B/UB rations lower than 1.0), however small progressive increases (i.e. DLK1) or decreases (i.e. LMO2, MYC) in the modification were detected though the time course. Interestingly, ALU repeat sequences, which account for ∼25% of the human genome, show a progressive increase in H4K8ac in VPA-treated cells, indicating that at least some repeat elements are susceptible to hyperacetylation in response to HDACi.


Genes are often sheltered from the global histone hyperacetylation induced by HDAC inhibitors.

Halsall J, Gupta V, O'Neill LP, Turner BM, Nightingale KP - PLoS ONE (2012)

Histone acetylation changes on up- and down-regulated genes during extended VPA treatment.Chromatin-immunoprecipitation analysis of H4K8ac on: (A), Up-regulated gene (DLK1), (B), Down-regulated genes (LMO2, MYC) or (C), repetitive elements (ALU) in response to VPA treatment (5 mM). Analysis was performed on either untreated cells (Control), or during VPA treatment (15, 60 & 240minutes). Primer locations are indicated on the gene diagrams. The abundance of a histone modification (‘Enrichment’) is calculated from the ratio of material detected in bound∶unbound fractions.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3316569&req=5

pone-0033453-g005: Histone acetylation changes on up- and down-regulated genes during extended VPA treatment.Chromatin-immunoprecipitation analysis of H4K8ac on: (A), Up-regulated gene (DLK1), (B), Down-regulated genes (LMO2, MYC) or (C), repetitive elements (ALU) in response to VPA treatment (5 mM). Analysis was performed on either untreated cells (Control), or during VPA treatment (15, 60 & 240minutes). Primer locations are indicated on the gene diagrams. The abundance of a histone modification (‘Enrichment’) is calculated from the ratio of material detected in bound∶unbound fractions.
Mentions: Finally, we extended this experiment to analyse three classes of genes – (i) a gene those that showed early and progressive up-regulation (DLK1,Fig. 5A), (ii) genes that show down-regulation (LMO2, MYC,Fig. 5B), and (iii) an abundant repetitive element, ALU (Yb8) (Fig. 5C). In all cases H4K8ac abundance was low at promoter-proximal loci (i.e. B/UB rations lower than 1.0), however small progressive increases (i.e. DLK1) or decreases (i.e. LMO2, MYC) in the modification were detected though the time course. Interestingly, ALU repeat sequences, which account for ∼25% of the human genome, show a progressive increase in H4K8ac in VPA-treated cells, indicating that at least some repeat elements are susceptible to hyperacetylation in response to HDACi.

Bottom Line: Different gene populations respond to each inhibitor, with as many genes down- as up-regulated.Surprisingly, HDACi rarely induced increased histone acetylation at gene promoters, with most genes examined showing minimal change, irrespective of whether genes were up- or down-regulated.Many genes seem to be sheltered from the global histone hyperacetyation induced by HDACi.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

ABSTRACT
Histone deacetylase inhibitors (HDACi) are increasingly used as therapeutic agents, but the mechanisms by which they alter cell behaviour remain unclear. Here we use microarray expression analysis to show that only a small proportion of genes (∼9%) have altered transcript levels after treating HL60 cells with different HDACi (valproic acid, Trichostatin A, suberoylanilide hydroxamic acid). Different gene populations respond to each inhibitor, with as many genes down- as up-regulated. Surprisingly, HDACi rarely induced increased histone acetylation at gene promoters, with most genes examined showing minimal change, irrespective of whether genes were up- or down-regulated. Many genes seem to be sheltered from the global histone hyperacetyation induced by HDACi.

Show MeSH