Adult epidermal cells proliferate and differentiate throughout and recapitulate the morphological and biochemical changes of embryonic development. Developmental regulation of genes includes a sequence of isoform transitions typified by the keratin multigene family, whose expression has distinct tissue-specific, temporal and spatial developmental patterns. The mechanisms controlling such differential gene expression are poorly understood. Tissue- specific and developmental activation of the gene expression has been attributed to the initiation of transcription and its modulation by the DNA sequence-specific interactions between cis- acting enhancer regulatory elements and trans-acting cellular transcriptional factors. Cellular factors regulating viral gene transcription may play an essential role controlling differential expression of cellular genes. DNA sequences recognized by trans- acting factors are often conserved among viral and developmentally co-regulated cellular genes. To define the function of the keratinocyte-specific trans-acting factor(s) including their role in development we will take advantage of the existence of consensus sequence homology between the 50K, 56K, 67K keratin and involucrin epidermal genes and a keratinocyte-dependent (KD) enhancer sequence element of the human papilloma virus-16 (HPV-16) p97 promoter. Viral KD-enhancer activation is restricted to keratinocytes. We hypothesize that the function of this factor(s) is to control coordinated expression of epidermal-specific genes activated during development and differentiation. To test this hypothesis we will: 1) determine which epithelial cell types are permissive for co- expression of cellular genes and the bacterial chloramphenicol transferase (CAT) reporter gene driven by KD-enhancer sequences, and identify the time during cell development that co-expression occurs. We will also define whether this co-expression is under control of the same factor(s); 2) Isolate, sequence and verify cDNA clones encoding the trans-acting factor(s); 3) Characterize the molecular mechanisms responsible for activation of epidermally expressed differentiation genes. 4) Determine whether epidermal transglutaminase (TGase I) is regulated by the same factor(s) and whether the synthesis and activity of the trans-acting factor(s) is developmentally regulated and modulated by inducers and suppressors of cell differentiation. The knowledge gained by this study will aid the understanding of normal and abnormal epidermal differentiation and development.
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