Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Cell Death Dis. 2010;1(9):e74. doi: 10.1038/cddis.2010.49.
The transcription factor p63 is required for proper epidermal barrier formation and maintenance. Herein, we used chromatin immunoprecipitation coupled with DNA sequencing to identify novel p63 target genes involved in normal human epidermal keratinocyte (NHEKs) growth and differentiation. We identified over 2000 genomic sites bound by p63, of which 82 were also transcriptionally regulated by p63 in NHEKs. Through the discovery of interleukin-1-α as a p63 target gene, we identified that p63 is a regulator of epithelial-mesenchymal crosstalk. Further, three-dimensional organotypic co-cultures revealed TCF7L1, another novel p63 target gene, as a regulator of epidermal proliferation and differentiation, providing a mechanism by which p63 maintains the proliferative potential of basal epidermal cells. The discovery of new target genes links p63 to diverse signaling pathways required for epidermal development, including regulation of paracrine signaling to proliferative potential. Further mechanistic insight into p63 regulation of epidermal cell growth and differentiation is provided by the identification of a number of novel p63 target genes in this study.
转录因子 p63 是表皮屏障形成和维持所必需的。在此，我们使用染色质免疫沉淀结合 DNA 测序来鉴定参与正常人类表皮角质形成细胞（NHEKs）生长和分化的新型 p63 靶基因。我们鉴定了超过 2000 个由 p63 结合的基因组位点，其中 82 个在 NHEKs 中也受到 p63 的转录调控。通过发现白细胞介素 1-α是 p63 的靶基因，我们鉴定出 p63 是上皮-间充质细胞相互作用的调节剂。此外，三维器官型共培养揭示了 TCF7L1，另一个新的 p63 靶基因，作为表皮增殖和分化的调节剂，为 p63 维持基底表皮细胞增殖潜力提供了一种机制。本研究中发现的新靶基因将 p63 与表皮发育所需的多种信号通路联系起来，包括对旁分泌信号向增殖潜力的调节。通过鉴定本研究中的一些新型 p63 靶基因，进一步深入了解了 p63 对表皮细胞生长和分化的调节。
