Changes to euchromatin on LAT and ICP4 following reactivation are more prevalent in an efficiently reactivating strain of HSV-1

• Published in: PloS one Vol. 5; no. 11; p. e15416
• Main Authors: Creech, Clinton C, Neumann, Donna M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04-11-2010; Public Library of Science (PLoS)
• Subjects: Abundance; Activation; Adrenergic Agonists - pharmacology; Analysis; Animals; Biology; Chromatin; Chromatin Assembly and Disassembly; Chromatin remodeling; Cornea - metabolism; Cornea - virology; Deoxyribonucleic acid; DNA; Epigenetic inheritance; Epigenetics; Epinephrine; Epinephrine - pharmacology; Euchromatin; Euchromatin - metabolism; Exons - genetics; Ganglia; Gene expression; Genomes; Genomics; Health aspects; Health sciences; Herpes viruses; Herpesvirus 1, Human - drug effects; Herpesvirus 1, Human - genetics; Herpesvirus 1, Human - physiology; Histones - metabolism; Humans; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; Infection; Infections; Iontophoresis; Kinases; Latency; Latent infection; Lysine - metabolism; Methylation - drug effects; MicroRNAs - genetics; MicroRNAs - metabolism; Post-translation; Promoter Regions, Genetic - genetics; Proteins; Rabbits; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; RNA, Viral - genetics; RNA, Viral - metabolism; Sensory neurons; Time Factors; Transcription; Translation; Trigeminal ganglion; Trigeminal Ganglion - metabolism; Trigeminal Ganglion - virology; Virology; Virus Activation - drug effects; Virus Activation - genetics; Virus Activation - physiology; Louisiana; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0015416

Epigenetic mechanisms, via post-translational histone modifications, have roles in the establishment and maintenance of latency of the HSV-1 genome in the sensory neurons. Considering that many post-translational histone marks are reversible in nature, epigenetic mechanisms may also play a critical role in the process of induced HSV-1 reactivation.
This study utilized the rabbit ocular model of HSV-1 infection and reactivation, induced by the transcorneal iontophoresis of epinephrine (TCIE), to characterize changes to chromatin that occur between 0.5 and 4 h following the application of the reactivation stimulus. Our goal was to explore the hypothesis that chromatin remodeling is an early and essential step in the process of HSV-1 reactivation. Analysis of the HSV-1 latently infected rabbit trigeminal ganglia (TG) showed that enrichment of the euchromatic marker H3K4me2 significantly decreased in the LAT 5'exon region (∼2.5-fold) and significantly increased in the lytic ICP4 promoter region (∼3-fold) by 1 h post-TCIE in the highly efficient reactivating McKrae strain of HSV-1. In contrast, we observed no significant change in the euchromatic marks of H3K4me2 associated with LAT 5'exon or ICP4 promoter regions of the poorly reactivating KOS strain of HSV-1 following TCIE through 4 h. The implication that these observed epigenetic changes were linked to transcriptional activity was confirmed by qRT-PCR examining both LAT and lytic transcript abundance following TCIE. We found a significant decrease in the abundance of LAT RNA by 2 h post-iontophoresis of epinephrine coupled to an increase in the transcript abundance of ICP4 in the McKrae strain of HSV-1. By comparison, we observed no change in the LAT or ICP4 transcript abundance of the poor reactivator KOS following iontophoresis of epinephrine through 4 h.
Our results implicate that chromatin remodeling is an early and essential step involved in the process of in vivo HSV-1 reactivation.