title: Conserved two-step regulatory mechanism of human epithelial differentiation.
abstract: Human epithelia are organized in a hierarchical structure, where stem cells generate terminally differentiated cells via intermediate progenitors. This two-step differentiation process is conserved in all tissues, but it is not known whether a common gene set contributes to its regulation. Here, we show that retinoic acid (RA) regulates early human prostate epithelial differentiation by activating a tightly coexpressed set of 80 genes (e.g., TMPRSS2). Response kinetics suggested that some of these genes could be direct RA targets, whereas others are probably responding indirectly to RA stimulation. Comparative bioinformatic analyses of published tissue-specific microarrays and a large-scale transcriptomic data set revealed that these 80 genes are not only RA responsive but also significantly coexpressed in many human cell systems. The same gene set preferentially responds to androgens during terminal prostate epithelial differentiation, implying a cell-type-dependent interplay between RA and tissue-specific transcription factor-mediated signaling in regulating the two steps of epithelial differentiation.
authors: YCR Cancer Research Unit, Department of Biology, University of York, York, North Yorkshire YO10 5DD, UK.
authors: Jayant K
authors: JK
authors: Rane
authors: YCR Cancer Research Unit, Department of Biology, University of York, York, North Yorkshire YO10 5DD, UK ; York Centre for Complex Systems Analysis and Department of Biology, University of York, York, North Yorkshire YO10 5DD, UK.
authors: Alastair P
authors: AP
authors: Droop
authors: YCR Cancer Research Unit, Department of Biology, University of York, York, North Yorkshire YO10 5DD, UK.
authors: Davide
authors: D
authors: Pellacani
authors: YCR Cancer Research Unit, Department of Biology, University of York, York, North Yorkshire YO10 5DD, UK.
authors: Euan S
authors: ES
authors: Polson
authors: Department of Urology, Castle Hill Hospital, Cottingham, Humberside HU16 5JQ, UK ; Hull York Medical School, University of Hull, Hull, Humberside HU6 7RX, UK.
authors: Matthew S
authors: MS
authors: Simms
authors: YCR Cancer Research Unit, Department of Biology, University of York, York, North Yorkshire YO10 5DD, UK.
authors: Anne T
authors: AT
authors: Collins
authors: York Centre for Complex Systems Analysis and Department of Biology, University of York, York, North Yorkshire YO10 5DD, UK.
authors: Leo S D
authors: LS
authors: Caves
authors: YCR Cancer Research Unit, Department of Biology, University of York, York, North Yorkshire YO10 5DD, UK.
authors: Norman J
authors: NJ
authors: Maitland
mesh_terms: D000728:Androgens / Q000378:metabolism / Q000494:pharmacology; D015415:Biomarkers; D002454:Cell Differentiation / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D009928:Organ Specificity / Q000235:genetics; D011467:Prostate / Q000166:cytology / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000728:Androgens; D015415:Biomarkers; D014212:Tretinoin