Retinoid‐responsive transcriptional changes in epidermal keratinocytes

Abstract

Retinoids (RA) have been used as therapeutic agents for numerous skin diseases, from psoriasis to acne and wrinkles. While RA is known to inhibit keratinocyte differentiation, the molecular effects of RA in epidermis have not been comprehensively defined. To identify the transcriptional targets of RA in primary human epidermal keratinocytes, we compared the transcriptional profiles of cells grown in the presence or absence of all-trans retinoic acid for 1, 4, 24, 48 and 72 hours, using large DNA microarrays. As expected, RA suppresses the protein markers of cornification; however the genes responsible for biosynthesis of epidermal lipids, long-chain fatty acids, cholesterol, and sphingolipids, are also suppressed. Importantly, the pathways of RA synthesis, esterification and metabolism are activated by RA; therefore, RA regulates its own bioavailability. Unexpectedly, RA regulates many genes associated with the cell cycle and programmed cell death. This led us to reveal novel effects of RA on keratinocyte proliferation and apoptosis. The response to RA is very fast: 315 genes were regulated already after 1 h. More than one-third of RA-regulated genes function in signal transduction and regulation of transcription. Using in silico analysis, we identified a set of over-represented transcription factor binding sites in the RA-regulated genes. Many psoriasis-related genes are regulated by RA, some induced, others suppressed. These results comprehensively document the transcriptional changes caused by RA in keratinocytes, add new insights into the molecular mechanism influenced by RA in the epidermis and demonstrate the hypothesis-generating power of DNA microarray analysis.

Establishment of esophageal-like non-keratinized stratified epithelium using normal human bronchial epithelial cells

“…ATRA promotes expression of an intestinal phenotype in gastrointestinal epithelial cells (3,7) and is known to suppress squamous differentiation in epidermal keratinocyte (16). We speculate that retinoids recirculating in duodenal secretions and as a constituent of gastric refluxate into the esophagus may directly influence esophageal epithelial function and differentiation.…”

Regulation of keratin expression by retinoids

“…As shown in Table 1, the effect of retinoids on keratins in vitro and in vivo is paradoxical. In vitro, retinoids reduces the expression of KRT5, KRT14, KRT6, KRT1 and KRT10 in cultured keratinocytes, [36][37][38][39][40] whereas KRT7, KRT13, KRT15 and KRT19 are induced. 27,38,40 By contrast, a different keratin profile is observed when retinoic acid is added to reconstructed human skin in vitro or topically to human skin in vivo.…”

“…In vitro, retinoids reduces the expression of KRT5, KRT14, KRT6, KRT1 and KRT10 in cultured keratinocytes, [36][37][38][39][40] whereas KRT7, KRT13, KRT15 and KRT19 are induced. 27,38,40 By contrast, a different keratin profile is observed when retinoic acid is added to reconstructed human skin in vitro or topically to human skin in vivo. Almost similar effects are generated in the two multilayered tissues including increased expression of K4, K6, K13, K16, K17 and K19 whereas no effects are observed on K5, K14, K1 and K10 proteins.…”

Increased retinoic acid levels through ablation of Cyp26b1 determine the processes of embryonic skin barrier formation and peridermal development

“…Retinoids are well known to influence skin development; however, contrasting results have been reported between in vivo and in vitro results (Imakado et al, 1995;Lee et al, 2009;Saitou et al, 1995;Yuspa et al, 1983;Yuspa and Harris, 1974), and the specific role of RA during embryonic skin differentiation has not been determined. Skin functions as a barrier to the physical environment, preventing dehydration and invasion of pathogenic microorganisms.…”