Chromatin and epigenetic regulation of Herpes Simplex Virus 1 lytic genomes

  • Author / Creator
    Hu, MiYao
  • Primary herpes simplex virus 1 (HSV-1) infections are common in childhood,
    affecting mainly the oropharyngeal mucosa. The virus is then transported to the
    neuronal bodies in the trigeminal ganglia, where it establishes lifelong latency. Although
    latent infections are asymptomatic, HSV-1 reactivates upon a variety of stresses,
    producing recrudescence of disease and spreading infection. Lytic infections are treated
    with several drugs, but latency and reactivation cannot be cured or prevented. HSV-1
    chromatin and epigenetic regulation during lytic and latent infections have been studied
    for decades. HSV-1 genomes are regularly chromatinized into inaccessible chromatin
    during latency but become more accessible during reactivation. Epigenetics thus likely
    play a major role in the regulation of HSV-1 transcription, replication, and reactivation
    from latency. Although HSV-1 DNA is non-regularly chromatinized in lytic infections,
    most current models assume a similar epigenetic regulation for HSV-1 as for cells.
    To evaluate the chromatinization of HSV-1 genomes during lytic infections, I
    performed nuclease protection assay coupled with bio-physical fractionation, to
    separate viral DNA-nucleoprotein complexes by hydrodynamic ratios, followed by deep
    sequencing (in collaboration with Dr. Depledge) of each fraction. Gene sampling and
    cluster analyses indicated that chromatin dynamics relate to the transcriptional
    competency of HSV-1 genomes, not the transcriptional levels of any individual genes or
    groups of genes. The transcriptionally competent genomes are in highly dynamic, and
    accessible, chromatin and the incompetent ones in far less dynamic, or accessible,
    chromatin. Moreover, chromatin insulator elements such as the CCCTC binding factor
    (CTCF) flank highly transcribed genome regions from mostly non-transcribed ones. My
    findings indicate that chromatin is a key regulator of HSV-1 transcription during lytic
    infections in that chromatin provide a first level of regulation, dictating transcriptional
    competency. I thus uncovered a new level of viral transcription regulation. During
    reactivation, the HSV-1 chromatin also changes from regular, mostly inaccessible,
    chromatin to a far more dynamic, and accessible, state. My findings during the lytic
    infections thus also provide a framework to better understand HSV-1 latency and

  • Subjects / Keywords
  • Graduation date
    Spring 2022
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.