Recent evidence has shown that alterations in epigenetic states can alter the ability of stem cell populations to differentiate into specific cell lineages and in some circumstances lead to the de-differentiation of differentiated cell types into more pluripotent stem cells. The molecular pathways controlling such epigenetic/chromatin remodeling events are still unclear. The forkhead or Fox gene family of transcriptional regulatory factors regulate tissue specific gene transcription and are important for self-renewal and differentiation of stem/progenitor cell populations during development. We have shown that the Foxp1/2/4 subfamily of Fox factors are highly expressed in developing skin and hair follicles. Recent evidence from our lab as well as others demonstrated that Foxp1/2/4 and the related Foxp3 factor interact with chromatin remodeling complexes, including NuRD and NCoR to repress gene specific expression during cell differentiation. Evidence from our lab shows that Foxp1/2/4 interact with components of the NuRD complex, mediating transcriptional repression of important target genes in the lung and heart. Our preliminary data suggest that Foxp1/2/4-NuRD interactions have profound affects on lung development as demonstrated by defects in Foxp1-HDAC2 and Foxp2-HDAC2 compound mutant mice. These studies illustrate one of the few examples of the chromatin remodeling complex NuRD interacting with a sequence specific DNA binding transcription factor. Given these fundamental roles for Foxp1/2/4 in development of the cardiovascular and pulmonary systems, we predict that they will play a similarly critical role in regulation of hair follicle development. To explore the role of Foxp1/2/4 in skin and hair follicle development, we propose to 1) determine the roles for Foxp1/2/4 in skin and hair follicle development by deleting these genes in epidermal specific knockout mice and 2) Determine the roles for HDAC1/2 in skin and hair follicle development through in vivo loss of function analyses.

Public Health Relevance

These experiments aim to uncover basic molecular mechanisms regulating development, homeostasis and stem cell function in mamamlian skin and hair follicles. The information obtained in these studies has the potential to reveal novel therpeutic targets for hair loss diseases and skin cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Center Core Grants (P30)
Project #
5P30AR057217-05
Application #
8499266
Study Section
Special Emphasis Panel (ZAR1-KM-D)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$64,352
Indirect Cost
$24,132
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ellebrecht, Christoph T; Bhoj, Vijay G; Nace, Arben et al. (2016) Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353:179-84
Lo, Agnes S; Mao, Xuming; Mukherjee, Eric M et al. (2016) Pathogenicity and Epitope Characteristics Do Not Differ in IgG Subclass-Switched Anti-Desmoglein 3 IgG1 and IgG4 Autoantibodies in Pemphigus Vulgaris. PLoS One 11:e0156800
Cho, Michael Jeffrey; Ellebrecht, Christoph T; Hammers, Christoph M et al. (2016) Determinants of VH1-46 Cross-Reactivity to Pemphigus Vulgaris Autoantigen Desmoglein 3 and Rotavirus Antigen VP6. J Immunol 197:1065-73
Billings, Paul C; Sanzari, Jenine K; Kennedy, Ann R et al. (2015) Comparative analysis of colorimetric staining in skin using open-source software. Exp Dermatol 24:157-9
Suzuki, Daisuke; Sahu, Raju; Leu, N Adrian et al. (2015) The carboxy-terminus of p63 links cell cycle control and the proliferative potential of epidermal progenitor cells. Development 142:282-90
Gay, Denise L; Yang, Chao-Chun; Plikus, Maksim V et al. (2015) CD133 expression correlates with membrane beta-catenin and E-cadherin loss from human hair follicle placodes during morphogenesis. J Invest Dermatol 135:45-55
Ortiz, Myrna L; Kumar, Vinit; Martner, Anna et al. (2015) Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17-producing CD4+ T cells. J Exp Med 212:351-67
Agarwal, Priti; Rashighi, Mehdi; Essien, Kingsley I et al. (2015) Simvastatin prevents and reverses depigmentation in a mouse model of vitiligo. J Invest Dermatol 135:1080-8
Wong, Waihay J; Richardson, Theresa; Seykora, John T et al. (2015) Hypoxia-inducible factors regulate filaggrin expression and epidermal barrier function. J Invest Dermatol 135:454-61
Hammers, Christoph M; Chen, Jing; Lin, Chenyan et al. (2015) Persistence of anti-desmoglein 3 IgG(+) B-cell clones in pemphigus patients over years. J Invest Dermatol 135:742-9

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