title: Changes to euchromatin on LAT and ICP4 following reactivation are more prevalent in an efficiently reactivating strain of HSV-1.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Our results implicate that chromatin remodeling is an early and essential step involved in the process of in vivo HSV-1 reactivation.
authors.affiliation: Department of Ophthalmology (LSU Eye Center of Excellence), Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Clinton C
authors.initials: CC
authors.lastname: Creech
authors.forename: Donna M
authors.initials: DM
authors.lastname: Neumann
mesh_terms: D000322:Adrenergic Agonists / Q000494:pharmacology; D000818:Animals; D042002:Chromatin Assembly and Disassembly; D003315:Cornea / Q000378:metabolism / Q000821:virology; D004837:Epinephrine / Q000494:pharmacology; D022041:Euchromatin / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D012668:Trigeminal Ganglion / Q000378:metabolism / Q000821:virology; D014775:Virus Activation / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: D000322:Adrenergic Agonists; D022041:Euchromatin; D006657:Histones; D017874:Immediate-Early Proteins; D035683:MicroRNAs; D012367:RNA, Viral; C048925:herpes simplex virus, type 1 protein ICP4; C477253:latency associated transcript, herpes simplex virus-1; D008239:Lysine; D004837:Epinephrine