Dynamic Regulation of Histone Lysine Methylation in Saccharomyces cerevisiae Public Deposited

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  • March 20, 2019
Creator
  • Gardner, Kathryn Elizabeth
    • Affiliation: School of Medicine, Department of Biochemistry and Biophysics
Abstract
  • DNA within eukaryotic nuclei is wrapped around histone proteins to form chromatin. Recent advances have greatly extended our understanding of both histone lysine methylation as an important post-translational modification that affects chromatin functionality and the enzymes responsible for placement of these marks. This particular modification plays important roles in maintenance of genome integrity, transcriptional regulation, and epigenetic memory. In the budding yeast Saccharomyces cerevisiae, histone lysine methylation has been shown thus far to occur on lysine residues 4, 36, and 79 of histone H3 (H3K4, H3K36, and H3K79, respectively) and is coupled tightly to the process of transcription. Prior to completion of the studies contained herein, both the reversibility of histone lysine methylation and the presence of methyl marks on other lysine residues remained poorly understood. Histone methylation was long considered to be a static modification. However, identification of a novel enzyme capable of removing methyl marks from modified lysine residues challenged this thought. Intriguingly, the identified demethylase activity was solely conferred by the enzyme's JumonjiC (JmjC) domain, a signature motif present in a large family of proteins, suggesting that other JmjC-domain-containing proteins could also act as histone demethylases. In budding yeast, the JmjC-domain-containing protein Jhd1 was the first identified histone demethylase with specificity for the mono- and dimethyl states of H3K36. To extend the concept of reversibility of histone methylation in yeast to other modified residues in distinct methylation states, here the budding yeast JmjC-domain-containing proteins Rph1 and Jhd2 are characterized as active histone demethylases with specificity for di- and trimethylated H3K36 and H3K4, respectively. Importantly, evidence is provided that Rph1-mediated demethylation of H3K36 putatively functions in transcription elongation and that Jhd2 is necessary for proper silencing of telomeric regions. Beyond demonstrating that histone methylation can be actively reversed, evidence is also provided that additional sites of lysine methylation exist. Namely, lysine 37 of histone H2B is identified as a novel site of histone methylation in budding yeast with evolutionary conservation in humans. Altogether, the work described in this dissertation supports the dynamic nature of histone lysine methylation and existence of additional sites of lysine methylation in budding yeast.
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biochemistry and Biophysics."
Advisor
  • Strahl, Brian
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  • Chapel Hill, NC
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  • Open access
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