Epigenetic regulation of latent HSV-1 gene expression.
Like other alpha-herpesviruses, Herpes Simplex Virus Type 1 (HSV-1) possesses the ability to establish latency in sensory ganglia as a non-integrated, nucleosome-associated episome in the host cell nucleus. Transcription of the genome is limited to the Latency-Associated Transcript (LAT), while the lytic genes are maintained in a transcriptionally repressed state. This partitioning of the genome into areas of active and inactive transcription suggests epigenetic control of HSV-1 latent gene expression. During latency viral transcription is not regulated by DNA methylation but likely by post-translational histone modifications. The LAT region is the only region of the genome enriched in marks indicative of transcriptional permissiveness, specifically dimethyl H3 K4 and acetyl H3 K9, K14, while the lytic genes appear under-enriched in those same marks. In addition, facultative heterochromatin marks, specifically trimethyl H3 K27 and the histone variant macroH2A, are enriched on lytic genes during latency. The distinct epigenetic domains of the LAT and the lytic genes appear to be separated by chromatin insulators. Binding of CTCF, a protein that binds to all known vertebrate insulators, to sites within the HSV-1 genome likely prevents heterochromatic spreading and blocks enhancer activity. When the latent viral genome undergoes stress-induced reactivation, it is possible that CTCF binding and insulator function are abrogated, enabling lytic gene transcription to ensue. In this review we summarize our current understanding of latent HSV-1 epigenetic regulation as it pertains to infections in both the rabbit and mouse models. CTCF insulator function and regulation of histone tail modifications will be discussed. We will also present a current model of how the latent genome is carefully controlled at the epigenetic level and how stress-induced changes to it may trigger reactivation.
Bloom
David C
DC
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610-0266, USA. dbloom@ufl.edu
Giordani
Nicole V
NV
Kwiatkowski
Dacia L
DL
D000818:Animals; D001483:Base Sequence; D044127:Epigenesis, Genetic; D015967:Gene Expression Regulation, Viral; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D017735:Virus Latency / Q000235:genetics*
D035683:MicroRNAs; C477253:latency associated transcript, herpes simplex virus-1