Research in the Molecular Genetics Section focuses on the mechanisms involved in gene expression of the alpha-herpesviruses: herpes simplex (HSV) and varicella zoster (VZV). As with all classes of herpesviruses, infection with HSV or VZV results in a primary infection followed by the establishment of a lifelong latent infection. Periodically, these latent viruses can reactivate or re-enter the lytic replication state, resulting in recurrent disease.
For herpes simplex virus, infection results in establishment of latency specifically in neurons of sensory ganglia, and reactivation produces disease that can range from mild oral or genital lesions to keratoconjunctivitis, blindness, neurological issues, and encephalitis.
As with its cellular hosts, viral gene expression is tightly regulated, and expression is dictated by a complex series of cellular and viral regulatory proteins that promote the expression of several classes of genes in a sequential manner (Immediate Early – Early – DNA replication – Late). The expression of Immediate Early (IE) genes is induced rapidly upon initial lytic infection. Importantly, coordinated expression of these genes is also critical for the initiation of reactivation from latency.
IE genes are exceptionally complex and are regulated by multiple families of transcription factors and coactivators.
A critical component of this reguatory network is the cellular transcriptional activator HCF-1. While multiple DNA binding transcription factors regulate IE genes, this coactivator HCF-1 interacts with and modulates the transcriptional potential.
In addition to these direct factors, the virus is also regulated by an overlay of regulation that is determined by the host cell’s chromatin modulation machinery. Recent data have demonstrated that HCF-1 interacts with or is a component of numerous cellular chromatin modulation complexes, and it is in this capacity that it plays a significant role in modulating viral IE gene expression. Studies in the MGS are focused on the role of HCF-1-mediated chromatin control of HSV and other herpesvirus infection.
In addition to its role in regulation of the viral IE gene expression upon initial infection, HCF-1 also plays a significant role in replication of the viral genome, presumably via required chromatin modulation of DNA replication. The protein interacts with histone chaperones and localizes to foci of viral DNA synthesis at later times in infection. Continuing projects investigate the HCF-1 role and complexes in both viral and cellular DNA replication.
While HCF-1 is a critical component of the viral lytic replication cycle, it is also hypothesized to be a determinant of the latency-reactivation cycles. The MGS has demonstrated that HCF-1 is uniquely sequestered in the cytoplasm of sensory neurons where the virus establishes latency and is rapidly transported to the nucleus upon stimulation that results in viral reactivation. The MGS continues to investigate the role of HCF-1, its associated factors, and chromatin modulation components in the control of latency-reactivation.
These studies have also led to the development of novel chromatin modulation inhibitors that block viral gene expression and provide proof of principle for the development of epigenetic inhibitors as novel antivirals.
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Dr. Kristie received his Ph.D. from the Committee on Virology at the University of Chicago for his work with Dr. Bernard Roizman on the regulation of herpes simplex virus gene expression. As a postdoctoral fellow with Dr. Philip Sharp at the Center for Cancer Research, Massachusetts Institute of Technology, Dr. Kristie focused on the interaction of components involved in the formation of transcriptional enhancer complexes. Dr. Kristie joined the NIAID Laboratory of Viral Diseases in 1993, became a senior investigator in 2000, and became chief of the Molecular Genetics Section in 2001.
For insights into the molecular mechanisms regulating the transcriptional program of herpesviruses that have led to the identification of new therapeutic targets
Jodi Vogel, Staff ScientistJesse Arbuckle, Postdoctoral FellowAnne-Marie Turner, Postdoctoral FellowRoberto Alfonso-Dunn, Postdoctoral FellowJoseph Newland, Staff
Daou S, Mashtalir N, Hammond-Martel I, Pak H, Yu H, Sui G, Vogel JL, Kristie TM, Affar el B. Crosstalk between O-GlcNAcylation and proteolytic cleavage regulates the host cell factor-1 maturation pathway. Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2747-52.
Kristie TM, Liang Y, Vogel JL. Control of alpha-herpesvirus IE gene expression by HCF-1 coupled chromatin modification activities. Biochim Biophys Acta. 2010 Mar-Apr;1799(3-4):257-65.
Peng H, Nogueira ML, Vogel JL, Kristie TM. Transcriptional coactivator HCF-1 couples the histone chaperone Asf1b to HSV-1 DNA replication components. Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2461-6.
Liang Y, Vogel JL, Narayanan A, Peng H, Kristie TM. Inhibition of the histone demethylase LSD1 blocks alpha-herpesvirus lytic replication and reactivation from latency. Nat Med. 2009 Nov;15(11):1312-7.
Whitlow Z, Kristie TM. Recruitment of the transcriptional coactivator HCF-1 to viral immediate-early promoters during initiation of reactivation from latency of herpes simplex virus type 1. J Virol. 2009 Sep;83(18):9591-5.
Narayanan A, Ruyechan WT, Kristie TM. The coactivator host cell factor-1 mediates Set1 and MLL1 H3K4 trimethylation at herpesvirus immediate early promoters for initiation of infection. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):10835-40.
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Last Updated September 11, 2012