Faculty Research Page

Britt Glaunsinger

Britt Glaunsinger

Howard Hughes Medical Institute Investigator and Professor of Biochemistry, Biophysics and Structural Biology*
*and of Plant and Microbial Biology

Lab Homepage: http://glaunsingerlab.berkeley.edu/

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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

cartoon summarizing lab interests

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. Gene expression is often considered 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 links between RNA decay and transcription in the gene expression cascade.  

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.

Viral activation and co-option of noncoding retrotransposons
 
Nearly half of the mammalian genome is composed of transposable elements, which are silent—at least most of the time. However, a subset of these elements that do not encode for any proteins, termed short interspersed nuclear repeats, or SINEs, can get activated in response to viral infection. Beyond documenting their striking upregulation throughout the genome during infection, we have revealed that these noncoding RNAs contribute to mammalian gene regulation in the nucleus and interface with innate immune signaling pathways in the cytoplasm.  We are currently working towards defining the functions of these and other virus-activated noncoding RNAs.
 

Selected Publications

Mendez AS, Vogt C, Bohne J, and Glaunsinger BA. (2018) Site specific target binding controls RNA cleavage efficiency by the Kaposi’s sarcoma-associated herpesvirus endonuclease SOX. Nucleic Acids Research, 2018 Oct 13. doi: 10.1093/nar/gky932. (bioRxiv doi: https://doi.org/10.1101/320929)
 
Gilbertson S, Federspiel JD, Hartenian H, Cristea IM, and Glaunsinger B. (2018) Changes in mRNA abundance drive shuttling of RNA binding proteins, linking cytoplasmic RNA degradation to transcription. eLife 2018;7:e37663.
 
Castañeda AF and Glaunsinger BA. (2018) The interaction between ORF18 and ORF30 is required for late gene transcription in Kaposi’s sarcoma-associated herpesvirus. J Virol. 2018 Oct 10. pii: JVI.01488-18. (bioRxiv doi: https://doi.org/10.1101/401976
 
Hesser CR, Karijolich J, Dominissini D, He C, Glaunsinger BA. (2018) N6-methyladenosine modification and the YTHDF2 reader protein play cell type specific roles in lytic viral gene expression during Kaposi's sarcoma-associated herpesvirus infection. PLoS Pathogens. Apr 16;14(4):e1006995. 
 
Muller M and Glaunsinger B. (2017) Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases. PLoS Pathogens.  Aug 25;13(8):e1006593.
 
Gaglia M, Rycroft C, and Glaunsinger B. (2015) Transcriptome-wide cleavage site mapping on cellular mRNAs reveals features underlying sequence-specific cleavage by the viral ribonuclease SOX. PLOS Pathogens; Dec 8;11(12):e1005305
 
Abernathy E, Gilbertson S, Alla R, Glaunsinger B.  2015.  Viral Nucleases Induce an mRNA Degradation-Transcription Feedback Loop in Mammalian Cells. Cell Host & Microbe. 18(2):243-53.
 
Karijolich J, Abernathy E, and Glaunsinger B. (2015) Infection-Induced Retrotransposon-Derived Noncoding RNAs Enhance Herpesviral Gene Expression via the NF-kB Pathway. PLoS Pathogens; 11(11): e1005260.
 
Muller M, Hutin S, Marigold O, Li KH, Burlingame A, Glaunsinger BA.  2015.  A ribonucleoprotein complex protects the interleukin-6 mRNA from degradation by distinct herpesviral endonucleases. PLoS Pathogens. 11(5):e1004899.
 
Davis ZH, Verschueren E, Jang GM, Kleffman K, Johnson JR, Park J, Von Dollen J, Maher CM, Johnson T, Newton W et al..  2015.  Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Molecular Cell. 57(2):349-60.
 

 

Photo credit: Mark Hanson at Mark Joseph Studios.

Last Updated 2019-03-12