Transcriptional Regulation in Eukaryotic Evolution and Disease

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Complex organisms consist of many diverse cell types, but the genetic information within these cells is identical. How does this occur? Part of the answer to this question lies in transcriptional regulation. The basic transcriptional control unit is the promoter. In their "default" state, promoters are wound tightly in chromatin which must be removed before transcriptional activation. Pioneer transcription factors facilitate this by binding to DNA in chromatin, but the mechamism they use to open chromatin and initiate transcription is unclear. I demonstrated they accomplish this by recruiting chromatin remodelers. This is a general mechanism that pioneer factors use to diversify gene expression programs. Enhancers are another transcriptional control unit that act over long distances. Transposable elements---features that copy themselves---were previously thought to be parasitic entities, but they are often coopted for host function. I found that a family of transposons has generated a network of circadian enhancers. These enhancers arose by mutation of proto-motifs in the ancestral transposon sequence. This highlights a previously underappreciated mechanism of transposon cooption for host transcription regulation. Viral infection profoundly alters host gene transcription. This is driven both by the immune response and by viral proteins that modulate host transcription to facilitate viral replication. I demonstrated that a SARS-CoV-2 protein, ORF3a, interacts with TRIM22, and that TRIM22 is an essential regulator of the innate immune response. By antagonizing TRIM22, SARS-CoV-2 disables one arm of the immune response, which contributes to the virulence and pathogenicity of SARS-CoV-2.

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275 pages


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enhancers; regulatory evolution; RNA polymerase; transcription; transposable elements; virology


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Union Local


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Committee Chair

Lis, John

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Feschotte, Cedric
Grimson, Andrew

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Biochemistry, Molecular and Cell Biology

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Ph. D., Biochemistry, Molecular and Cell Biology

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Doctor of Philosophy

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Government Document




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Attribution 4.0 International


dissertation or thesis

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