Faculty Research Page

Britt Glaunsinger
Howard Hughes Medical Institute Investigator and Professor of Biochemistry, Biophysics and Structural Biology*
*and of Plant and Microbial Biology
Research Interests
The Glaunsinger lab studies the creative strategies viruses use to manipulate gene expression in host cells. Our focus is RNA-based regulation of gene expression, both at the level of RNA synthesis and turnover. We are interested in viral factors that directly target RNA, as well as how viruses interface with and hijack cellular pathways to control gene expression. We primarily study gammaherpesviruses, including Kaposi's sarcoma-associated herpesvirus, which is a major cause of AIDS-associated cancers. We anticipate that these studies will enhance our understanding of virus-host interactions, as well as provide insight into how gene expression pathways are normally regulated in human cells.
Current Projects
Viruses and the Art of Gene Expression
Mechanisms of Virus-Induced mRNA Destruction
The ability to regulate RNA stability has the potential to impact gene expression on a global scale, but is also critical for fine-tuning cellular responses to specific stimuli as well as eliminating flawed and potentially deleterious transcripts. Lytic gammaherpesvirus infection promotes widespread destruction of messenger RNAs (mRNAs), a phenotype driven primarily by the viral endonuclease SOX. By probing how SOX and other functionally related viral proteins drive messenger RNA degradation, we hope to reveal novel interplay between viruses and host gene regulatory pathways, as well as identify cellular factors with capacity to broadly influence message stability.
We are also probing how cells sense and respond to broad changes in RNA levels. Most of us think about gene expression as a linear series of events starting with mRNA synthesis in the nucleus and ending with mRNA degradation after translation in the cytoplasm. However, by manipulating mRNA abundance in the cytoplasm--something herpesviruses do very efficiently--we are finding surprising interconnectivity in the gene expression cascade.
The Great Escape—How do Select RNAs Evade Degradation?
Although the vast majority of messages are degraded during lytic gamma-herpesvirus infection, we know that some transcripts escape degradation and accumulate robustly. Prominent among these is human interleukin 6 (IL-6), a B cell growth factor that has been demonstrated to play a role in the pathogenesis of several KSHV-associated neoplasms. We identified a specific element within IL-6 that renders it directly refractory to degradation by multiple viral endonucleases. Using the IL-6 escape element as a model, we are exploring how networks of RNA-protein interactions can impact endonuclease targeting.
Novel Modes of Transcriptional Regulation During Infection
A universal feature of dsDNA viruses is that they all encode a class of genes whose expression is intimately linked to replication of the viral genome. These are termed ‘late genes’, and their transcription is robustly stimulated after the onset of DNA replication but otherwise restricted. Recent studies indicate that late gene transcriptional regulation in these viruses is unique, as it incorporates both molecular mimicry and selective recruitment of key host transcriptional machinery in a manner not previously observed in viral or host gene expression. In particular, one of the viral proteins required for late gene transcription directly binds both Pol II and promoter DNA, making this a unique viral transcriptional coordinator—and the first example of its kind in higher eukaryotes or eukaryotic viruses. We are currently working to understand how this hybrid virus-host preinitiation complex is assmembed and regulated. This viral model is anticipated to reveal new modes of transcriptional control, which may well have parallels in mammalian gene expression.
Selected Publications
Lee YJ, Glaunsinger BA. 2009. Aberrant herpesvirus-induced polyadenylation correlates with cellular messenger RNA destruction. PLoS Biology. 7(5):e1000107.
Photo credit: Mark Hanson at Mark Joseph Studios.
Last Updated 2015-09-01