Expanding the function of histone H3 lysine 36 methylation in Saccharomyces cerevisiae Public Deposited

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  • March 19, 2019
Creator
  • McDaniel, Stephen
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Eukaryotic DNA is wrapped around an octamer of histone proteins, two each of H2A, H2B, H3, and H4, to form chromatin. The cell must negotiate the chromatin landscape to facilitate all DNA templated processes, including replication, repair, and transcription. The histone proteins themselves can be heavily modified by small chemical moieties like methyl, phospho, or ubiquitin groups, called post-translational modifications (PTMs). PTMs can both alter the electrostatic properties of chromatin, promoting an opening or closing of specific chromatin regions and/or as specific docking sites for effector proteins. The spatial-temporal localization of histone PTMs is highly regulated and when disrupted can lead to a variety of diseases. Methylation of histone H3 at lysine 36 (H3K36me) is a very well conserved and highly regulated histone modification laid down by the histone methyltransferase Set2 in the budding yeast S. cerevisiae. H3K36me occurs co-transcriptionally, thus marking actively transcribed genes. Though, H3K36me is associated with active transcription, it actually functions as a repressive mark, recruiting the Isw1b chromatin remodeling complex and the Rpd3S histone deacetylase complex (HDAC) to chromatin following the elongating RNA polymerase II (RNAPII) complex, preventing the binding of RNAPII to cryptic promoters within gene bodies. Here, three new aspects of H3K36me are elucidated. First, a new H3K36me binding protein is characterized, Pdp3. Pdp3 binds to H3K36me and is a member of the newly described NuA3b histone acetyltrasferase (HAT) complex. The binding of Pdp3 to H3K36me is necessary for the function of NuA3b for in the absence of Pdp3 or H3K36me, NuA3 target genes are down regulated and several other transcriptional defects are observed. Second, the role of the second plant homeodomain (PHD) finger in Rco1 of the Rpd3S complex is elucidated. Like the first PHD finger, it is necessary for Rpd3S localization to chromatin in addition to preventing aberrant transcription from occurring within gene bodies. Finally, a novel role for Set2 and H3K36me in the nutrient stress response is uncovered. Surprisingly, it is found that Set2 genetically interacts with several pathways critical for nutrient response signaling such as the Tor1, Tor2, and Slt2 mitogen-activated protein (MAP kinase) pathways. Without Set2 present, the kinetics and overall levels of signaling in these pathways is altered. Together, the work in this dissertation expands our understanding of the role H3K36me plays in transcription and cellular signaling and hopefully will guide future work in higher eukaryotes to better understand and treat human diseases.
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  • In Copyright
Advisor
  • Marzluff, Bill
  • Duronio, Robert
  • Cook, Jean
  • Strahl, Brian
  • Bultman, Scott
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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