Paul M. Lieberman, Ph.D.

Research in the Lieberman laboratory centers on understanding how 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 lymphoma, nasopharyngeal carcinoma, Hodgkin lymphoma, post-transplant lymphoproliferative disorder for EBV, and Kaposi’s Sarcoma for KSHV. Both EBV and KSHV are known to encode viral genes that have oncogenic activity, including activation of proliferation signal and survival factors. These oncogenic factors can be silenced or actively expressed depending on variations in immune control and epigenetic states. How the tumor microenvironment impacts the control of the viral chromatin and gene regulatory controls is a major area of interest.

The Lieberman lab has focused on viral chromosome architecture controlled by cellular proteins CTCF and cohesins that link different regulatory elements to coordinate networked gene expression. CTCF and cohesins can also regulate the interaction of the viral episomes with host chromosomes that can affect cellular gene expression, particularly at oncogenes and tumor suppressor gene loci. Some of these epigenetic interactions can lead to longer-term genetic changes, such as deletions and amplifications that can also contribute to viral carcinogenesis.

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.

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.

Maintenance of telomere structures that maintain the ends of linear chromosomes is also important for human genome stability. The Lieberman lab found that telomeres share some common features with viral episome maintenance elements. They are investigating how telomere chromatin structures vary depending on host cell conditions and may limit the replication and expansion of telomere repeats, which can impact the cellular replicative senescence.

The Lieberman lab also studies how the telomere-repeat containing non-coding RNA, TERRA, is expressed from telomere repeats and how it alters telomere chromatin structure. They are also investigating the role of TERRA as an inflammatory molecule that can be released from cells through exosomes and may affect the local immune microenviroment.

EBV infection is strongly associated with Multiple Sclerosis (MS) and Systemic Lupus Erythematosis (SLE). The Lieberman lab is investigating how EBV infected B-lymphocytes are the pathogenic drivers for MS and SLE. They have characterized patient samples for EBV gene expression and B-cell subtypes, and found that EBV infected antibody producing cells and antigen presenting cells may be responsible for the inflammatory cascades that drive auto reactivity to the CNS in MS and to nuclear antigens in SLE. Ongoing work focuses on single-cell transcriptomics and immunophenotyping of patient derived B-lymphocytes and the development of an appropriate mouse model for EBV immune dysregulation and CNS trafficking.

The Lieberman laboratory is also pursuing the development of small molecule inhibitors of the EBV encoded episome maintenance 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. One of these inhibitors is in a Phase I/II clinical trial for EBV-associated cancers. Efforts are ongoing to design additional selective inhibitors of EBV-and KSHV-associated malignancies and autoimmune disease.