Antonini Dario, Sirico Anna, Aberdam Edith, Ambrosio Raffaele, Campanile Carmen, Fagoonee Sharmila, Altruda Fiorella, Aberdam Daniel, Brissette Janice L, Missero Caterina
IRCCS SDN, Napoli, Italy.
CEINGE Biotecnologie Avanzate, Napoli, Italy.
Nucleic Acids Res. 2015 Jan;43(2):862-74. doi: 10.1093/nar/gku1396. Epub 2015 Jan 7.
p63 is a crucial regulator of epidermal development, but its transcriptional control has remained elusive. Here, we report the identification of a long-range enhancer (p63LRE) that is composed of two evolutionary conserved modules (C38 and C40), acting in concert to control tissue- and layer-specific expression of the p63 gene. Both modules are in an open and active chromatin state in human and mouse keratinocytes and in embryonic epidermis, and are strongly bound by p63. p63LRE activity is dependent on p63 expression in embryonic skin, and also in the commitment of human induced pluripotent stem cells toward an epithelial cell fate. A search for other transcription factors involved in p63LRE regulation revealed that the CAAT enhancer binding proteins Cebpa and Cebpb and the POU domain-containing protein Pou3f1 repress p63 expression during keratinocyte differentiation by binding the p63LRE enhancer. Collectively, our data indicate that p63LRE is composed of additive and partly redundant enhancer modules that act to direct robust p63 expression selectively in the basal layer of the epidermis.
p63是表皮发育的关键调节因子，但其转录调控机制仍不清楚。在此，我们报告鉴定出一种远程增强子（p63LRE），它由两个进化保守模块（C38和C40）组成，协同作用以控制p63基因的组织和层特异性表达。这两个模块在人和小鼠角质形成细胞以及胚胎表皮中均处于开放且活跃的染色质状态，并与p63紧密结合。p63LRE活性在胚胎皮肤中依赖于p63表达，在人类诱导多能干细胞向上皮细胞命运的定向分化中也同样如此。对参与p63LRE调控的其他转录因子的研究发现，CAAT增强子结合蛋白Cebpa和Cebpb以及含POU结构域的蛋白Pou3f1在角质形成细胞分化过程中通过结合p63LRE增强子来抑制p63表达。总的来说，我们的数据表明p63LRE由相加且部分冗余的增强子模块组成，这些模块在表皮基底层中选择性地指导p63的强劲表达。
