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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 modification distribution on genes up-regulated by VPA.Chromatin immunoprecipitation analysis of histone modifications on two VPA-responsive genes: KIF3C and RERE. Graphs indicate the enrichment of histone modifications at specific primer pairs in untreated cells (Control), and after eight hours of VPA treatment (+VPA). Histone modification enrichment is shown as a bound∶unbound ratio. The primers used are indicated on gene diagrams, which also indicate the transcription start site (TSS), exons (Empty boxes), and untranslated regions (Filled boxes). 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-g003: Histone modification distribution on genes up-regulated by VPA.Chromatin immunoprecipitation analysis of histone modifications on two VPA-responsive genes: KIF3C and RERE. Graphs indicate the enrichment of histone modifications at specific primer pairs in untreated cells (Control), and after eight hours of VPA treatment (+VPA). Histone modification enrichment is shown as a bound∶unbound ratio. The primers used are indicated on gene diagrams, which also indicate the transcription start site (TSS), exons (Empty boxes), and untranslated regions (Filled boxes). The abundance of a histone modification (‘Enrichment’) is calculated from the ratio of material detected in bound∶unbound fractions.

Mentions: The expression analyses described indicate that VPA stimulates transcriptional responses at a subset of genes. We used chromatin immunoprecipitation to assess whether transcriptional activation correlated with increased histone acetylation at two VPA up-regulated genes - KIF3C (7-fold increase) and RERE (2-fold increase) (Fig. 3). Epigenome mapping indicates that the TSS of active genes show enhanced levels of acetylated histones [13], so we focussed on these regions. Acetyl marks are not functionally interchangeable, so we analysed a highly abundant acetyl mark (H4K16ac), along with marks found in moderately acetylated (H4K8ac) or hyperacetylated chromatin (H3K9ac) [23]–[25].


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 modification distribution on genes up-regulated by VPA.Chromatin immunoprecipitation analysis of histone modifications on two VPA-responsive genes: KIF3C and RERE. Graphs indicate the enrichment of histone modifications at specific primer pairs in untreated cells (Control), and after eight hours of VPA treatment (+VPA). Histone modification enrichment is shown as a bound∶unbound ratio. The primers used are indicated on gene diagrams, which also indicate the transcription start site (TSS), exons (Empty boxes), and untranslated regions (Filled boxes). 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-g003: Histone modification distribution on genes up-regulated by VPA.Chromatin immunoprecipitation analysis of histone modifications on two VPA-responsive genes: KIF3C and RERE. Graphs indicate the enrichment of histone modifications at specific primer pairs in untreated cells (Control), and after eight hours of VPA treatment (+VPA). Histone modification enrichment is shown as a bound∶unbound ratio. The primers used are indicated on gene diagrams, which also indicate the transcription start site (TSS), exons (Empty boxes), and untranslated regions (Filled boxes). The abundance of a histone modification (‘Enrichment’) is calculated from the ratio of material detected in bound∶unbound fractions.
Mentions: The expression analyses described indicate that VPA stimulates transcriptional responses at a subset of genes. We used chromatin immunoprecipitation to assess whether transcriptional activation correlated with increased histone acetylation at two VPA up-regulated genes - KIF3C (7-fold increase) and RERE (2-fold increase) (Fig. 3). Epigenome mapping indicates that the TSS of active genes show enhanced levels of acetylated histones [13], so we focussed on these regions. Acetyl marks are not functionally interchangeable, so we analysed a highly abundant acetyl mark (H4K16ac), along with marks found in moderately acetylated (H4K8ac) or hyperacetylated chromatin (H3K9ac) [23]–[25].

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