Transcriptional regulation of epidermal differentiation by ZNF750
Abstract/Contents
- Abstract
- The epidermis is a continuously self-renewing tissue that forms a critical barrier between the inside of the body and the outside world. Self-renewing progenitor keratinocytes are located in the basal layer of the epidermis, and a subset of their progeny will differentiate and migrate outwards to form the epidermal permeability barrier. The process of epidermal differentiation is tightly regulated and disruption of this process can lead to skin cancer or other skin disorders. Thus, we sought to identify and functionally characterize novel regulators of epidermal differentiation. To identify novel regulators of epidermal differentiation, we searched for genes whose expression changed during this process. ZNF750 was identified by its significant increase in expression during epidermal differentiation. ZNF750 was completely uncharacterized, with the exception of several studies linking mutations in ZNF750 to psoriasis. Depletion of ZNF750 in organotypic epidermal tissue results in decreased expression of late epidermal differentiation genes. Enforced expression of ZNF750 in progenitor keratinocytes is sufficient to induce epidermal differentiation, and ZNF750-driven epidermal differentiation depends on a single C2H2 motif. The transcription factor p63 binds to the ZNF750 promoter and induces ZNF750 expression. ZNF750 then binds to the KLF4 promoter and induces KLF4 expression. To further understand how ZNF750 regulates epidermal differentiation, we identified ZNF750 direct target genes and interacting proteins. ZNF750 binds near differentiation genes it activates and progenitor genes it represses at a sequence-specific DNA motif. ZNF750-interacting proteins were identified to include KLF4, RCOR1, KDM1A, and CTBP1/2. ZNF750 protein-protein interactions occur through two PLNLS motifs and ZNF750 binds DNA through its C2H2 motif. KLF4 co-localizes ~10bp from ZNF750 near differentiation genes to facilitate their activation, but is unnecessary for progenitor gene repression. In contrast, KDM1A co-localizes with ZNF750 at progenitor genes to facilitate their repression. RCOR1 and CTBP1/2 are required for both effects. Thus, ZNF750 as a p63 target gene that interacts with KLF4, RCOR1, and CTBP1/2 to induce epidermal differentiation genes and interacts with KDM1A, RCOR1, and CTBP1/2 to repress epidermal progenitor genes.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2015 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Boxer, Lisa Danielle |
|---|---|
| Associated with | Stanford University, Department of Biology. |
| Primary advisor | Khavari, Paul A |
| Thesis advisor | Khavari, Paul A |
| Thesis advisor | Chang, Howard |
| Thesis advisor | Gozani, Or Pinchas |
| Thesis advisor | Morrison, Ashby J |
| Advisor | Chang, Howard |
| Advisor | Gozani, Or Pinchas |
| Advisor | Morrison, Ashby J |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Lisa Danielle Boxer. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2015. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2015 by Lisa Danielle Boxer
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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