Dissertation
Genetic and genomic studies of histone H3 methylation and acetylation
Washington State University
Doctor of Philosophy (PhD), Washington State University
12/2008
DOI:
https://doi.org/10.7273/000005951
Abstract
Histone H3 methylation plays important roles in gene transcription regulation. A large body of literature has been devoted to investigating the functions of histone H3 methylation at individual residues. In contrast, very little is known about how combinations of methylated lysine residues act in concert to regulate genome-wide transcription. We have systematically mutated all three methylated histone lysine residues in Saccharomyces cerevisiae, and discovered that simultaneous mutation of H3K4, H3K36, and H3K79 to arginine (H3 K4,36,79R) is lethal. The histone H3 K4,36,79R mutant leads to a progressive transcription defect that initiates in telomere regions and later spreads further into the chromosome. In addition, this mutation results in a delay of the cell cycle progression. These defects are partially mediated by the increased binding of the SIR silencing complex to euchromatin regions adjacent to telomeres in the H3 K4,36,79R mutant. Intriguingly, the presence of intact histone lysine methyltransferase proteins, but not methylation activity, is required for the lethality of the H3 K4,36,79R mutant. These and other data suggest that the three histone H3 methylated lysine residues in concert are critical to transcription regulation in yeast. Besides methylated lysine residues, acetylated lysine residues in histone H3 are also integral to yeast gene expression and other biological processes. Multiple lines of evidence suggested that histone H3 acetylated and methylated lysine residues might functionally interact to regulate gene transcription. We tested this possible genetic interaction between histone mutants by simultaneously mutating acetylated or methylated lysine residues. The data indicate that various growth defects of the histone H3 methylated lysine mutant are rescued by the H3 acetylated lysine mutant. In contrast, histone H3 acetylated and methylated lysine residues generally make independent contributions to yeast gene transcription. Furthermore, the gene expression changes are preferentially associated with genomic regions in which histone H3 lysine residues are hypoacetylated and hypomethylated. Finally, our results reveal that acetylated and methylated lysine residues have different impacts on the binding of the SIR silencing complex to telomere heterochromatin regions, in turn regulating telomeric silencing. Taken together, completion of the work described in this thesis provides novel and valuable information regarding to the combinatorial functions of histone H3 methylation and acetylation.
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Details
- Title
- Genetic and genomic studies of histone H3 methylation and acetylation
- Creators
- Yi Jin
- Contributors
- John J. Wyrick (Chair)John A Browse (Committee Member) - Washington State University, Institute of Biological ChemistryMICHAEL L. KAHN (Committee Member) - Washington State University, Institute of Biological ChemistryMICHAEL J. SMERDON (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Program in Molecular Plant Sciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 209
- Identifiers
- 99901055131101842
- Language
- English
- Resource Type
- Dissertation