Chromatin accessibility dynamics underlie a decline in neural stem cell migratory ability with age
Abstract/Contents
- Abstract
- Chromatin accessibility is emerging as a critical component of genetic regulation through its role in physically permitting or restricting access to genomic loci. Here I present two studies from my thesis work on chromatin regulation: one that leverages chromatin accessibility dynamics to identify novel age-related changes to adhesion and migratory pathways in murine neural stem cells, and another that uses dynamic chromatin accessibility changes throughout C. elegans development to identify and spatiotemporally characterize novel functional enhancers. In the murine brain, the adult sub-ventricular zone (SVZ) is a neurogenic niche comprised of a number of rare cell types including quiescent and activated neural stem cells (qNSCs and aNSCs). Epigenomic regulation is tightly linked to cell fate decisions and has been demonstrated to become dysregulated with age in a variety of systems. Yet, how the epigenomic landscape of NSCs changes upon activation and with age remains unknown. Here I profile the chromatin landscape of rare populations of SVZ niche cells, including qNSCs and aNSCs, isolated from young and old adult murine brains. Aging causes a differential response in the global chromatin landscape of qNSCs and aNSCs involving accessibility changes in adhesion and migration pathways. Functionally, old aNSCs migrate slower than young aNSCs while the opposite is true for the quiescent population. This age-related decline in aNSC migratory speed is accompanied by increased staining of the focal adhesion protein vinculin. Inhibiting the cytoskeletal regulator ROCK in old aNSCs improves migration speeds, promotes neurite outgrowth, and reduces actin stress fibers associated with biophysical adhesion. In another model system, the nematode C. elegans, I use chromatin accessibility dynamics throughout development from embryogenesis to adulthood to generate a list of putative enhancers that play a role in development. I then generate multiple transgenic fluorescent reporter strains in order to validate the cis-regulatory activity of these genomic regions and spatiotemporally characterize the activity of multiple novel functional enhancers during C. elegans development. Validated functional enhancers display unique spatiotemporal regulatory activity that corresponds to accessibility dynamics at those chromatin peaks in vivo during C. elegans development. Together, these results demonstrate that chromatin accessibility dynamics can be a powerful tool to uncover previously unknown biology and identify novel cis-regulatory elements during aging and development in multiple systems.
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 | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Yeo, Robin William Alexander Koerner |
|---|---|
| Degree supervisor | Brunet, Anne, 1972- |
| Thesis advisor | Brunet, Anne, 1972- |
| Thesis advisor | Bassik, Michael |
| Thesis advisor | Kundaje, Anshul, 1980- |
| Thesis advisor | Sage, Julien |
| Thesis advisor | Wyss-Coray, Anton |
| Degree committee member | Bassik, Michael |
| Degree committee member | Kundaje, Anshul, 1980- |
| Degree committee member | Sage, Julien |
| Degree committee member | Wyss-Coray, Anton |
| Associated with | Stanford University, Department of Genetics |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Robin W. Yeo. |
|---|---|
| Note | Submitted to the Department of Genetics. |
| Thesis | Thesis Ph.D. Stanford University 2020. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Robin William Alexander Koerner Yeo
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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