Date of Award
Doctor of Philosophy (PhD)
A key development for our understanding of the mechanisms that control gene expression has been the finding that the histones recruit proteins with effector functions to chromatin. This is mediated primarily by post-translational modifications that occur on the histone N-terminal domains (“tails”). Single or combinations of histone tail modifications serve as scaffolds for protein complexes controlling transcription or co-transcriptional processes, thus impacting gene expression. Histone tail modifications are regulated by multiple, often overlapping pathways in the cell, and as such, present an important regulatory “node” through which the cell is able to integrate and respond to environmental signals. However, a consequence of this is that any artificial or naturally occurring molecule that “mimics” the histone tails has the potential to strongly impact gene function and the cell’s response to the environment. Indeed, we were able to identify a novel pathway exploited by the influenza virus to directly dampen the host transcriptional response. The non-structural protein 1 (NS1) of the Influenza virus contains a histone H3-like sequence that is able to bind to and disrupt the activity of the human PAF1 transcription elongation complex (PAF1C). Loss of PAF1C function leads to an impaired antiviral response and increased influenza viral replication. Genome-wide binding analyses indicate that PAF1 is inducibly recruited to anti-viral and inflammatory genes during infection, and that its presence coincides with the recruitment of RNA polymerase II (Pol II) and the expression of target genes. Altogether, our findings imply that exploiting histone mimicry could be a general strategy for pathogens to subvert or co-opt host-processes for their own benefit. Our studies also strongly suggest that proper regulation of transcription elongation by PAF1C is an important rate-limiting step in the transcriptional response to pathogens.
Ho, Jessica Sook Yuin, "Chromatin Control of the Antiviral Response to Influenza" (2014). Student Theses and Dissertations. 213.