Genetic interaction mapping identifies the INO80 chromatin remodeling complex as a key metabolic regulator in the yeast Saccharomyces cerevisiae
Abstract/Contents
- Abstract
- Eukaryotic genomes function in a chromatin environment. Chromatin modifying enzymes are critical for imparting epigenetic regulation to maintain a dynamic and responsive chromatin state, allowing cells to carry out chromatin templated processes such as transcription, DNA replication and chromosome segregation. In this work, we further our understanding of the function and mechanism of chromatin remodelers. We investigate the INO80 chromatin remodeler in the budding yeast Saccharomyces cerevisiae using genetic, biochemical, and molecular approaches. In Chapter 1, we report an expansive genetic screen with chromatin remodelers and metabolic regulators. We find that the INO80 chromatin remodeling complex is composed of multiple distinct functional subunit modules. We demonstrate that the INO80 complex is a central component of metabolic homeostasis, including mitochondrial maintenance and TORC1 signaling, that influences histone acetylation and may contribute to disease when disrupted. In Chapter 2, we identify functional roles of the Arp5 and Ies6 subunits of INO80 in maintaining metabolic stability. We find Arp5-Ies6 form a distinct subcomplex, the relative occupancy of which correlates with nucleosome positioning and expression levels of over 1000 genes which are significantly enriched in energy metabolism pathways. In Chapter 3, we delineate a hierarchical assembly of Arp5-Ies6 into INO80. We identify conserved domains of Arp5 that are needed to couple ATP hydrolysis with productive nucleosome remodeling by INO80. Our results illustrate the dynamic nature of the INO80 complex, and demonstrate for the first time that a chromatin-remodeler regulates glycolytic and respiratory capacity, thereby maintaining metabolic stability.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Beckwith, Sean Lu | |
|---|---|---|
| Associated with | Stanford University, Department of Biology. | |
| Primary advisor | Morrison, Ashby J | |
| Thesis advisor | Morrison, Ashby J | |
| Thesis advisor | Gozani, Or Pinchas | |
| Thesis advisor | Lipsick, Joseph Steven, 1955- | |
| Thesis advisor | Stearns, Tim | |
| Advisor | Gozani, Or Pinchas | |
| Advisor | Lipsick, Joseph Steven, 1955- | |
| Advisor | Stearns, Tim |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Sean Lu Beckwith. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Sean Lu Beckwith
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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