HDAC inhibitors stimulate viral transcription by multiple mechanisms

Lata Balakrishnan,Barry Milavetz

doi:10.1186/1743-422x-5-43

Abstract

BackgroundThe effects of histone deacetylase inhibitor (HDACi) treatment on SV40 transcription and replication were determined by monitoring the levels of early and late expression, the extent of replication, and the percentage of SV40 minichromosomes capable of transcription and replication following treatment with sodium butyrate (NaBu) and trichostatin A (TSA).ResultsThe HDACi treatment was found to maximally stimulate early transcription at early times and late transcription at late times through increased numbers of minichromosomes which carry RNA polymerase II (RNAPII) transcription complexes and increased occupancy of the transcribing minichromosomes by RNAPII. HDACi treatment also partially relieved the normal down-regulation of early transcription by T-antigen seen later in infection. The increased recruitment of transcribing minichromosomes at late times was correlated to a corresponding reduction in SV40 replication and the percentage of minichromosomes capable of replication.ConclusionThese results suggest that histone deacetylation plays a critical role in the regulation of many aspects of an SV40 lytic infection.

Highlights

The effects of histone deacetylase inhibitor (HDACi) treatment on SV40 transcription and replication were determined by monitoring the levels of early and late expression, the extent of replication, and the percentage of SV40 minichromosomes capable of transcription and replication following treatment with sodium butyrate (NaBu) and trichostatin A (TSA)
Stimulation of SV40 transcription following inhibition of histone deacetylation We have previously shown that treatment of SV40 infected cells with the HDACi NaBu resulted in a large increase in the amount of hyperacetylated H4 and H3 associated with transcribing SV40 minichromosomes [12]
Since treatment with an HDACi frequently results in the stimulation of transcription of receptive genes [13], we first determined whether NaBu treatment had a similar effect on SV40 early and late transcription

Summary

Introduction

The effects of histone deacetylase inhibitor (HDACi) treatment on SV40 transcription and replication were determined by monitoring the levels of early and late expression, the extent of replication, and the percentage of SV40 minichromosomes capable of transcription and replication following treatment with sodium butyrate (NaBu) and trichostatin A (TSA). We know little about the specific mechanisms underlying the relationship between HDAC inhibition (HDACi) and alterations in gene expression at the molecular level. Sodium butyrate (NaBu) and Trichostatin A (TSA) are commonly used reversible inhibitors of HDAC activity. TSA, a hydroxamic acid is a fermentation product of Streptomyces and a potent inhibitor of HDAC activity. NaBu has been extensively used as a HDAC inhibitor (HDACi), though it is far less efficient (required in millimolar quantities) in its inhibition capabilities as compared to TSA (required only in nanomolar quantities). DNA micro array studies have shown that (page number not for citation purposes)

Methods

Results

Conclusion