AP-1 transcription factor is a barrier to nuclear reprogramming to pluripotency
Abstract/Contents
- Abstract
- Mechanistic insight into nuclear reprogramming from one cell state to another is of fundamental and clinical importance. Here we use the heterokaryon cell-fusion model of nuclear reprogramming to capture the dynamic architecture of chromatin accessibility and gene expression. At the onset of reprogramming, we detect a transient, genome-wide increase in accessible sites enriched for the AP-1 transcription factor motif assayed by ATAC-seq. Inhibition of AP-1 by expression of a dominant-negative results in an increase in OCT4 expression in heterokaryons. Moreover, in human iPSC reprogramming, dominant negative AP-1 can replace exogenous OCT4 in the reprogramming cocktail. We identify c-Jun as the inhibitory AP-1 family member and show that its repressive activity is mediated through interaction with NURD complex component MBD3 in a phosphorylation dependent manner. Our findings reveal that AP-1, which is induced at the onset of reprogramming and traditionally thought to be an activator, creates a JUN-MBD3 repressor complex that inhibits nuclear reprogramming to pluripotency through direct targeting of an OCT4 distal regulatory element. These findings reveal an unexpected role for Jun as a repressive epigenetic gatekeeper of reprogramming to pluripotency.
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 | Markov, Glenn |
|---|---|
| Associated with | Stanford University, Department of Genetics. |
| Primary advisor | Blau, Helen M |
| Thesis advisor | Blau, Helen M |
| Thesis advisor | Kundaje, Anshul, 1980- |
| Thesis advisor | Sage, Julien |
| Thesis advisor | Snyder, Michael, Ph. D |
| Advisor | Kundaje, Anshul, 1980- |
| Advisor | Sage, Julien |
| Advisor | Snyder, Michael, Ph. D |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Glenn Markov. |
|---|---|
| Note | Submitted to the Department of Genetics. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Glenn Jeremy Markov
- License
- This work is licensed under a Creative Commons Attribution Non Commercial Share Alike 3.0 Unported license (CC BY-NC-SA).
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