The long-term objective of our research program is to understand transcriptional control of epidermal development and differentiation within the epidermis. One critical function of the epidermis is to form an effective permeability barrier;defective epidermal barrier contributes to many skin diseases. The formation of the barrier, which is intricately linked to the terminal differentiation of epidermal keratinocytes, depends on structural proteins, proteases, lipid composition and cell-cell adhesion in the granular layer of the epidermis. While we have gained significant understanding of the cell biology of the barrier, much less is known about the mechanisms that control its formation. In particular, we do not understand well the transcriptional control that underlies the coordinated expression multiple genes encoding barrier components. In the last funding period of this award, we discovered the Grainyhead-like transcription factor Grainyhead-like Epithelial Transactivator 1 (Get1/Grhl3) based on its interaction with the LIM-only factor LMO4. During development, both Get1 and LMO4 are expressed in the developing epidermis, suggesting a role in epidermal formation. Deletion of the Get1 gene leads to alterations in the expression of multiple genes linked to terminal differentiation and barrier formation of the epidermis. Furthermore, simultaneous deletion of both Get1 and LMO4 leads to a more severe defect in terminal differentiation, indicating that we have identified key transcription factors for control of terminal differentiation and barrier formation. Based on these findings we hypothesize that Get1 directly regulates multiple terminal differentiation genes in a stage-specific manner, and that Get1 forms a complex with LMO4 to regulate at least a subset of these genes. In this renewal application, we propose three Specific Aims: 1) to determine the mechanisms underlying deregulation of multiple terminal differentiation genes in Get1 knockout mice;2) to define the temporal requirement for Get1 in regulation of epidermal terminal differentiation;and 3) to determine whether Get1 and LMO4 act in a complex to regulate terminal differentiation of the epidermis. These investigations will enhance our understanding of defective epidermal barrier formation, and may aid the discovery of treatment options. Defective skin barrier is a significant public health problem that occurs in several inherited and acquired diseases of the skin, as well as in premature infants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044882-15
Application #
8115905
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
1998-08-01
Project End
2013-03-31
Budget Start
2011-08-01
Budget End
2013-03-31
Support Year
15
Fiscal Year
2011
Total Cost
$298,721
Indirect Cost
Name
University of California Irvine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Klein, Rachel Herndon; Hu, William; Kashgari, Ghaidaa et al. (2017) Characterization of enhancers and the role of the transcription factor KLF7 in regulating corneal epithelial differentiation. J Biol Chem :
Klein, Rachel Herndon; Stephens, Denise N; Ho, Hsiang et al. (2016) Cofactors of LIM Domains Associate with Estrogen Receptor ? to Regulate the Expression of Noncoding RNA H19 and Corneal Epithelial Progenitor Cell Function. J Biol Chem 291:13271-85
Spitler, Ryan; Ho, Hsiang; Norpetlian, Frederique et al. (2015) Combination of low level light therapy and nitrosyl-cobinamide accelerates wound healing. J Biomed Opt 20:051022
Peyrard-Janvid, Myriam; Leslie, Elizabeth J; Kousa, Youssef A et al. (2014) Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development. Am J Hum Genet 94:23-32
Salmans, Michael L; Yu, Zhengquan; Watanabe, Kazuhide et al. (2014) The co-factor of LIM domains (CLIM/LDB/NLI) maintains basal mammary epithelial stem cells and promotes breast tumorigenesis. PLoS Genet 10:e1004520
Watanabe, Kazuhide; Villarreal-Ponce, Alvaro; Sun, Peng et al. (2014) Mammary morphogenesis and regeneration require the inhibition of EMT at terminal end buds by Ovol2 transcriptional repressor. Dev Cell 29:59-74
Watanabe, Kazuhide; Biesinger, Jacob; Salmans, Michael L et al. (2014) Integrative ChIP-seq/microarray analysis identifies a CTNNB1 target signature enriched in intestinal stem cells and colon cancer. PLoS One 9:e92317
Gordon, William M; Zeller, Michael D; Klein, Rachel H et al. (2014) A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasia. J Clin Invest 124:5205-18
Bhandari, A; Gordon, W; Dizon, D et al. (2013) The Grainyhead transcription factor Grhl3/Get1 suppresses miR-21 expression and tumorigenesis in skin: modulation of the miR-21 target MSH2 by RNA-binding protein DND1. Oncogene 32:1497-507
Gordon, William; Galitovskiy, Valentin; Edwards, Robert et al. (2013) The tobacco carcinogen nitrosamine induces a differential gene expression response in tumour susceptible A/J and resistant C3H mouse lungs. Eur J Cancer 49:725-33

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