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Gene silencing induced by oxidative DNA base damage: association with local decrease of histone H4 acetylation in the

Andriy Khobta1, Simon Anderhub, Nataliya Kitsera

  • 1Johannes Gutenberg University of Mainz, Institute of Pharmacy, Staudingerweg 5, 55128 Mainz, Germany. khobta@uni-mainz.de

Nucleic Acids Research
|March 27, 2010
PubMed

Insights

Oxidatively damaged DNA, like 8-oxoguanine (8-oxoG), impairs gene expression. This study reveals that histone H4 deacetylation in the promoter region causes this gene silencing, suggesting a chromatin-mediated mechanism.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • DNA Damage and Repair

Background:

  • Oxidized DNA bases, such as 7,8-dihydro-8-oxoguanine (8-oxoG), are naturally produced in cells.
  • These oxidative lesions can lead to mutations and affect gene expression.
  • Impaired gene expression from damaged DNA has been observed, but the underlying mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the mechanism behind the impaired expression of oxidatively damaged DNA.
  • To determine if chromatin structure changes are involved in the silencing of damaged genes.
  • To explore the role of histone modifications in the repression of damaged DNA.

Main Methods:

  • Transfection of human host cells with oxidatively damaged plasmid DNA.
  • Analysis of histone modifications (acetylation and methylation) in the promoter and transcribed regions of the damaged gene.
  • Quantification of histone H3, H4, and H1 levels.
  • Treatment with trichostatin A, a histone deacetylase inhibitor, to assess the impact on gene expression.

Main Results:

  • Expression of damaged plasmid DNA was impaired due to decreased retention and selective gene silencing.
  • A significant decrease (25%) in histone H4 acetylation was observed in the proximal promoter region of the damaged gene.
  • Other tested chromatin modifications showed no significant changes.
  • Trichostatin A treatment partially restored the expression of the damaged DNA.

Conclusions:

  • Oxidatively damaged DNA is subject to selective gene silencing in human cells.
  • This silencing is associated with specific changes in chromatin structure, particularly reduced histone H4 acetylation in the promoter region.
  • Histone deacetylase activity plays a role in the persistent repression of oxidatively damaged DNA, suggesting a chromatin-mediated silencing mechanism.

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