GSBS Dissertations and Theses

Approval Date

12-17-2015

Document Type

Doctoral Dissertation

Academic Program

Interdisciplinary Graduate Program

Department

Biochemistry and Molecular Pharmacology

First Thesis Advisor

Oliver Rando, MD, PhD

Keywords

Chromatin, Gene Expression Regulation, Regulator Genes, Histones, Saccharomyces cerevisiae Proteins, Histone-Lysine N-Methyltransferase

Subjects

Dissertations, UMMS; Chromatin; Gene Expression Regulation; Genes, Regulator; Histones; Saccharomyces cerevisiae Proteins; Histone-Lysine N-Methyltransferase

Abstract

The following work demonstrates that chromatin regulators play far more pronounced roles in dynamic gene expression than they do in steady-state. Histone modifications have been associated with transcription activity. However, previous analyses of gene expression in mutants affecting histone modifications show limited alteration. I systematically dissected the effects of 83 histone mutants and 119 gene deletion mutants on gene induction/repression in response to diamide stress in yeast. Importantly, I observed far more changes in gene induction/repression than changes in steady-state gene expression. The extensive dynamic gene expression profile of histone mutants and gene deletion mutants also allowed me to identify specific interactions between histone modifications and chromatin modifiers. Furthermore, by combining these functional results with genome-wide mapping of several histone modifications in the same time course, I was able to investigate the correspondence between histone modification occurrence and function. One such observation was the role of Set1-dependent H3K4 methylation in the repression of ribosomal protein genes (RPGs) during multiple stresses. I found that proper repression of RPGs in stress required the presence, but not the specific sequence, of an intron, an element which is almost unique to this gene class in Saccharomyces cerevisiae. This repression may be related to Set1’s role in antisense RNA-mediated gene silencing. Finally, I found a potential role for Set1 in producing or maintaining uncapped mRNAs in cells through a mechanism that does not involved nuclear exoribonucleases. Thus, deletion of Set1 in xrn1Δ suppresses the accumulation of uncapped transcripts observed in xrn1Δ. These findings reveal that Set1, along with other chromatin regulators, plays important roles in dynamic gene expression through diverse mechanisms and thus provides a coherent means of responding to environmental cues.

DOI

10.13028/M21G6J

Rights and Permissions

Copyright is held by the author, with all rights reserved.

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