Epigenetic Control of Viral Latency
Research in the Lieberman laboratory centers on understanding how the cancer-associated viruses, like Epstein-Barr virus (EBV) and Kaposi’s Sarcoma Associated Herpesvirus (KSHV), persist in a latent state and increases the risk of cancer cell evolution. EBV and KSHV establish latent infections that are associated with several human malignancies, including Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's disease, and post-transplant lymphoproliferative disorder for EBV, and Kaposi’s Sarcoma for KSHV.
The researchers have recently found that viral DNA replication and maintenance is regulated by interactions with cellular telomere binding proteins. Telomeres are the repetitive DNA sequences found at the ends of chromosomes. Telomeres protect chromosomes from loss of genetic information, and a similar process is thought to preserve the virus during latency. The Lieberman research team has worked out several biochemical pathways that control the stability, replication, and gene expression patterns of the latent virus. They have found that changes in viral chromatin structure alters the cancer-risk associated with latent infection.
Recent Scientific Advances
Virus Modulation of Host Chromosomes
The Lieberman lab continues to study EBV and KSHV genome maintenance proteins, EBNA1 and LANA, respectively. These proteins bind to the viral OriP, but they also bind to the cellular chromosome at unknown sites. The Lieberman lab has identified the cellular chromosome binding sites for both EBNA1 and LANA in latently infected B-lymphocytes. LANA was found to bind to host genes involved in gamma-interferon signaling and LANA may antagonize STAT1/STAT3 binding to host genes important for MHC peptide presentation and processing. EBNA1 may promote higher order structures, including interchromosome linkages that may promote translocations similar to those observed in Burkitt’s lymphoma.
Chromosome Conformation Control of Viral Latency
The role of chromosome architecture and higher-ordered structure is also important for genome maintenance. The Lieberman lab has studied the role of chromatin architecture proteins CTCF and cohesins in regulating viral genome structure and gene expression during latent infection. They have shown that CTCF and cohesins mediate long-distance interactions that are important for control of gene expression and maintenance of a stable latent infection. Loss of genome architecture leads to a change in gene expression and a transition from a circular to linear viral genome.
Telomere Maintenance and Dysfunction in Cancer
Maintenance of telomere structures that maintain the ends of linear chromosomes is also important for human genome stability. The Lieberman lab has investigate the chromatin structure of telomeres and the expression of a telomere repeat-containing non-coding RNA, termed TERRA. They have shown that TERRA is overexpressed in highly proliferating cells in human and mouse cancers. The TERRA form nuclear aggregates in cancer cells in mouse models of medulloblastoma, and TERRA RNA levels were highly over-expressed in human ovarian cancer biopsies. The regulation and function of TERRA expression, and its role in regulating telomere length and stability are the focus of future research.
Drug Discovery Research
The Lieberman laboratory is also pursuing the development of small molecule inhibitors of the EBV encoded origin binding protein EBNA1. The laboratory is collaborating with structural biologists and medicinal chemists to advance hits into lead compounds for testing in animal models of EBV lymphomagenesis. These small molecules will be considered for further development as inhibitors of EBV-associated malignancies.