A prion epigenetic switch drives inheritance of an activated chromatin state
Abstract/Contents
- Abstract
- The ability to establish and transmit molecular memory of transcription is critical for cell fate identity and development, and often goes awry in disease. From a single totipotent embryo, development shapes phenotypically distinct cellular lineages from a single common genome. This trajectory of diversification was first investigated by Aristotle, which he referred to as 'epigenesis, ' and later was mapped to modern biology and what we know as epigenetics by Waddington. In recent decades, the term epigenetics has been further refined in the light of growing molecular insights; it now commonly refers to the activities of transcription factors, non-coding RNAs, and the modification of chromatin to establish heritable transcriptional activity states. Of the known mechanisms for the establishment of epigenetic states, covalent modification of the unstructured tail region of histone proteins has proven to be a pervasive and flexible one. Methylation, ubiquitylation, and acetylation—among numerous others—all act in concert as part of what has been referred to as a 'histone code.' Dependent of the constellation of modifications on resident histones, the transcriptional machinery that recognizes them confers either repressive or activating activities to the local chromatin environment. Critical for transcription, this histone code is yet more potent, as it has the capacity to be transmitted across the complete reorganization of chromatin that occurs through cell division. The principle mechanism of this activity is the ability of chromatin modifying machinery to execute a 'read-write' mechanism. When the chromosome duplicates, parental modified histones are randomly dispersed between daughter strands. Parental marks are then read by a suite of factors, and writing enzymes are recruited to copy marks to the local newly synthesized histones. Although this mechanism has been observed across nearly all eukaryotes, importantly, it is restricted to exclusively repressive, histone-methylation-driven states. Whether other states, for example active transcription driven by hyperacetylated histones can be epigenetically inherited has remained unknown. Aside from chromatin, many epigenetic traits are instead linked to the activity of heritable alternative conformational states of proteins alone. Such proteins are by and large prions, which are proteins that can assume multiple stable conformations, at least one of which can self-template to drive an intrinsically bi-stable switch. Long engendering a tight association with devastating neurodegenerative disease, we now know that prions can instead give rise to an unappreciated form of epigenetics. Biologically functional prions and prion-like proteins have now been identified in bacteria, fungi, and metazoans where they regulate processes as diverse as translation, metabolism, and even long-term memory. Despite the conservation of this biology across life, it has been assumed that prions are rare within proteomes. By contrast, recent work has found that they are common, particularly among chromatin-templated processes (e.g. transcription factors, chromatin remodelers), suggesting a possible connection between prion conformational conversion and other epigenetic mechanisms. Here I have investigated one such prion that, through a regulated switching event, precipitates the establishment of an active, hyperacetylation-driven epigenetic state heritable through both mitotic and meiotic division. This prion, which we term [ESI+] for expressed sub-telomeric information, arose from the Snt1 scaffold protein. I identify a potential mechanism for its regulation through phosphorylation upon cell cycle arrest, and find that once activated the prion modifies the activity of Snt1 and its interactors in the Set3C complex, converting the complex from a repressor to an activator via recruitment of RNA pol II. This activity is most pronounced at sub-telomeres, where Snt1 and Set3C interfere with the conserved transcription regulator Rap1 binding. As a consequence of sub-telomeric activation, [ESI+] cells acquire broad tolerances to environmental stress, including antifungal drugs. Together, these results establish that prion conformational conversion can interface with chromatin, allowing for the inheritance of epigenetic states not previously considered heritable. While alone a striking example of how two forms of epigenetics can synergize to drive inheritance of active transcription, it by no means stands alone. Indeed, numerous chromatin-related proteins have prion-like properties, suggesting that this mechanism might be generally employed to regulate chromatin activity independently of other mechanisms. Further, even [ESI+] is likely not isolated to the laboratory, as dozens of wild strains of yeast exhibit elevated sub-telomeric expression evocative of the prion. While the limits of this biology remain to be explored, the example I present here strongly argues that it is far broader and more tightly integrated with other molecular systems than previously appreciated.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Harvey, Zachary Hugh |
|---|---|
| Degree supervisor | Jarosz, Daniel |
| Thesis advisor | Jarosz, Daniel |
| Thesis advisor | Brunet, Anne, 1972- |
| Thesis advisor | Mochly-Rosen, Daria |
| Thesis advisor | Wysocka, Joanna, Ph. D |
| Degree committee member | Brunet, Anne, 1972- |
| Degree committee member | Mochly-Rosen, Daria |
| Degree committee member | Wysocka, Joanna, Ph. D |
| Associated with | Stanford University, Department of Chemical and Systems Biology. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Zachary H. Harvey. |
|---|---|
| Note | Submitted to the Department of Chemical and Systems Biology. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by Zachary Hugh Harvey
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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