Graduate Thesis Or Dissertation


Role of Transcriptional Factor COUP-TF-interacting Proteins in Skin Permeability Barrier Development, and in Skin Carcinogenesis, and Role of Lipids in Atopic Dermatitis Public Deposited

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  • Mammalian skin is the largest organ of the body and serves as a barrier to protect the body against chemical, mechanical and pathogenic insults as well as water loss. The epidermis is formed from the primitive ectoderm into a multilayered stratified epithelium, consisting of basal, spinous, granular and outermost cornified cell layers. The epidermal permeability barrier (EPB) is established during embryogenesis and maintained through lifetime. Impaired formation of epidermal permeability barrier could lead to several common inflammatory skin disorders [e.g atopic dermatitis (AD) and psoriasis] and ultimately could contribute to skin carcinogenesis. A better understanding of the molecular mechanisms underlying the skin barrier formation and maintenance will be useful for the diagnosis and therapeutic targeting of certain cutaneous disorders. COUP-TF-interacting proteins 1 and 2 (CTIP1/BCL11A and CTIP2/BCL11B) are C2H2 zinc finger transcription factors. Previous studies have demonstrated that CTIP2 is highly expressed in mouse and human skin and is essential for the murine skin barrier development and homeostasis. Deletion of Ctip2 in the developing epidermis leads to impaired epidermal permeability barrier (EPB) function, prolonged inflammation and dysregulation of cutaneous wound repair. CTIP2 has been described as a tumor suppressor gene in association with hematological malignancies. The role of CTIP2 in skin carcinogenesis is yet to be determined. To investigate the role of CTIP2 in response to acute environmental stress and in chemical induced skin carcinogenesis, we utilized a transgenic mouse model where the CTIP2 was selectively ablated from adult epidermal keratinocytes using ligand inducible cre-recombinase system (Ctip2 [superscript ep-/-i] mice). Ctip2 [superscript ep-/-i] mice developed AD-like phenotype with altered EPB function and skin homeostasis. Loss of Ctip2 in adult epidermis also led to increased skin sensitivity to acute dose of TPA and/or UVB. Furthermore, Ctip2 [superscript ep-/-i] mice showed high susceptibility to DMBA/TPA induced skin carcinogenesis. Interestingly, we observed significant up-regulation of inflammatory mediators such as IL4, IL6 and TSLP in Ctip2 [superscript ep-/-i] tumor adjacent skin, suggesting that CTIP2 might control the initiation of chemical carcinogen-induced skin cancer in a cell-extrinsic manner by regulating inflammation in the tumor microenvironment. CTIP1, a homolog of CTIP2, is highly expressed in mouse and human skin, and a compensatory up-regulation of CTIP1 expression was observed in mouse skin lacking CTIP2. We therefore explored the role of CTIP1 in epidermal homeostasis and in skin barrier formation. Germline deletion of Ctip1 (Ctip1 [superscript -/-] mice) resulted in skin permeability barrier defects accompanied by impaired epidermal terminal differentiation and altered lipid composition. Moreover, transcriptional profiling of Ctip1 [superscript -/-] embryonic skin by RNA-sequencing identified altered expression of a subset of genes encoding (1) lipid-metabolism enzymes, (2) skin barrier associated transcription factors, and (3) junction proteins. Furthermore, integration of ChIP-seq data and RNA-seq data by bioinformatics analyses revealed that CTIP1 was recruited to the genomic locus of certain differentiation-associated and lipid-metabolism related genes that were altered in Ctip1 [superscript -/-] mice, including fos-related antigen 2 (Fosl2), transcription factor p63 (p63), fatty acid elongase 4 (Elovl4) and toll-like receptor 4 (Tlr4). Our results indicate that CTIP1 may regulate EPB formation and establishment via direct or indirect targeting of a subset of genes associated with epidermal differentiation and lipid metabolism. Lipids are critical components of epidermal barrier and altered lipid composition could lead to skin barrier dysfunction. Skin barrier defects in AD patients result in cutaneous infections with Staphylococcus aureus, which could further aggravate barrier dysfunction in AD. Defects in lipid composition and/or metabolism have been observed in both Ctip1 [superscript -/-] and Ctip2 [superscript -/-] mice models, leading to dysregulated skin barrier functions. In order to determine whether lipid endophenotypes of stratum corneum (SC) associated with the clinical AD subphenotypes of S.aureus colonization or barrier functions, we performed comprehensive analysis of SC lipids composition in AD subjects (with / without S.aureus colonization) and health controls by using modified ultra-performance liquid chromatography quadruple time of flight mass spectrometry (UPLC-QTOF-MS/MS). We identified some lipid subtypes associated with bacterial colonization, while others with altered skin barrier and increased trans-epidermal water loss, suggesting altered composition of epidermal lipids can contribute to barrier disruption and/or susceptibility to S.aureus colonization in AD. Altogether, above collection of the studies underscores the role of the transcriptional regulators in (1) skin barrier functions, (2) skin carcinogenesis, and establishes the connection between skin lipids and AD-pathogenesis in humans.
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