COMBINATORIAL REGULATION BY ENZYMES THAT MODULATE THE CHROMATIN LANDSCAPE AND GENE EXPRESSION

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  • March 22, 2019
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  • Runge, John
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • The eukaryotic genome is stored in the nucleus as chromatin, a dynamic structure of DNA and histone proteins. Chromatin contains a vast array of features that directs how, when, and where genomic DNA is made accessible by regulatory machinery. These features facilitate homeostatic cell programs, whereas their misregulation is a hallmark of cancer where endogenous regulatory programs are co-opted to promote aberrant signaling. In Chapter 1, I introduce four classes of proteins and protein complexes, among others, that regulate chromatin. I describe seminal discoveries that indicate these classes operate within elaborate networks that direct genomic output. In Chapter 2, I outline the roles that the class of ATP-dependent chromatin remodeling enzymes, nicknamed movers, serves in chromatin regulation. Chapters 3 and 4 describe our ongoing efforts to elucidate the mechanism by which a mover, named INO80-C, targets chromatin and identifies suitable genomic loci for regulation. We leveraged genomics approaches, biochemistry, and molecular biology to characterize the genomic targeting and molecular function of INO80-C in human cells. Chapter 3 details our observation that INO80-C is not a uniform biochemical complex at all sites across the genome, in contrast to expectations based on the literature. Chapter 4 demonstrates our efforts to delineate the function of INO80-C at its genomic targets, including our exploration of an antagonistic relationship with a histone methyltransferase named Polycomb Repressive Complex 2. Collectively, these data indicate that INO80-C engages in meaningful crosstalk with other chromatin regulators and features at its genomic targets. In Chapter 5, I draw conclusions from my research and place the findings into a broader context. Additionally, I describe the implications that my work may have on translational topics, with an emphasis on cancer biology.
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Advisor
  • Crawford, Gregory
  • Calabrese, Mauro
  • Magnuson, Terry
  • Davis, Ian
  • Kim, William
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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