Bidirectional control of keratinocyte differentiation and proliferation by transcription factor FOXQ1

皮肤是抵御物理、生物和化学侮辱的第一道屏障，对预防疾病至关重要。 脱水的症状。为了维持这一功能，表皮角质形成细胞需要进行分化。在分化过程中， 角质形成细胞中的基因表达程序从维持细胞增殖切换到终末 差异化。在基底层和上层表皮之间形成的钙梯度是一个主要因素。 角质形成细胞终末分化的潜在诱导。此外，皮肤动态平衡依赖于良好的- 由角质形成细胞和其他细胞产生的细胞因子介导的协调的细胞间通讯 皮肤常驻细胞。 我们已经确定转录因子FOXQ1(叉头盒蛋白家族的成员)利用 角质形成细胞分化转录调控的新型变阻器机制。因此，在现场 由于细胞外低钙，FOXQ1抑制了正常人表皮分化相关基因 角质形成细胞(NHKs)和永生化人角质形成细胞(HaCaT)。相反，在钙处理(即 分化诱导)NHK和HaCaT细胞，FOXQ1激活相同的一组基因。因此，具体来说， 目的1、研究FOXQ1对角质形成细胞转录调控的作用机制 差异化。 此外，我们证明在正常条件下，培养的角质形成细胞中FOXQ1的耗竭。 而其过表达则促进细胞增殖。此外，Foxq1-/-小鼠表现出 咪喹莫特治疗可导致银屑病样变的表皮增生减少 小鼠表皮的表型。 因此，在特定的目标2中，我们将产生角质形成细胞特异性的Foxq1基因敲除小鼠，并鉴定 促炎症细胞因子对FOXQ1的调节机制及对FoxQ1的调节作用 角质形成细胞过度增殖。

The skin forms the first barrier against physical, biological and chemical insults and is essential for prevention of dehydration. To maintain this function epidermal keratinocytes undergo differentiation. During differentiation, the gene expression programs in keratinocytes switch from maintenance of cell proliferation to terminal differentiation. Calcium gradient formed between the basal and upper epidermal layers is a major factor underlying induction of terminal differentiation in keratinocytes. In addition, skin homeostasis relies on well- orchestrated intercellular communications mediated by cytokines that are produced by keratinocytes and other skin resident cells. We have identified that transcription factor FOXQ1 (a member of the Forkhead Box family of proteins) utilizes a novel, rheostat-like mechanism of transcriptional regulation of keratinocyte differentiation. Thus, in presence of low extracellular calcium, FOXQ1 repressed genes associated with epidermal differentiation in normal human keratinocytes (NHKs) and immortalized human keratinocytes (HaCaT). On the contrary, in calcium-treated (i.e. differentiation-induced) NHK and HaCaT cells, FOXQ1 activated the same set of genes. Therefore, in Specific Aim 1, we will identify the mechanisms underlying transcriptional regulation by FOXQ1 of keratinocyte differentiation. In addition, we demonstrated that under normal conditions, depletion of FOXQ1 in cultured keratinocytes decreased whereas its overexpression increased cell proliferation. Moreover, Foxq1-/- mice demonstrated decreased epidermal hyperplasia in response to treatment with imiquimod which induces psoriasis-like phenotypes in mouse epidermis. Therefore, in Specific Aim 2, we will generate keratinocyte-specific Foxq1 knock-out mice and identify the mechanisms of FOXQ1 regulation by pro-inflammatory cytokines and the role of Foxq1 in regulation of keratinocyte hyper-proliferation.