Epigenetic regulation of epidermal homeostasis

描述（由申请人提供）：皮肤中的角质形成细胞通过激活增殖修复反应和刺激驻留免疫细胞启动炎症反应来应对环境损伤。这是由角质形成细胞表达的一系列细胞因子、趋化因子和应激诱导抗原介导的。参与这种反应的基因的快速激活和随后的抑制表明，它们在角化细胞中维持在一种表观遗传状态，这种状态为转录做好了准备，但对环境线索有反应。我们对角质形成细胞中染色质重塑剂Mi-2¿的研究为这一假设提供了强有力的支持。Mi-2¿通过维持这些通路中的基因处于抑制状态，在防止角化细胞应激反应和修复功能的不适当激活方面具有非常具体和核心的作用。Mi-2¿靶点之一是TSLP，在其他情况下被称为“促炎信号”，相反，它在解决Mi-2¿功能受阻时发生的表观遗传诱导的应激反应中起着关键的保护作用。Mi-2¿和TSLP在角化细胞稳态中的作用是通过三个特定目的来研究的。在第一个目标中，我们建立了由Mi-2¿In调控的基因

DESCRIPTION (provided by applicant): Keratinocytes in the skin are poised to respond to environmental insults by activating a proliferation-repair response and also by stimulating resident immune cells to initiate an inflammatory response. This is mediated by a panoply of cytokines, chemokines and stress-induced antigens expressed by keratinocytes. The rapid activation and subsequent suppression of the genes involved in this response implies that they are maintained in an epigenetic state in keratinocytes that is poised for transcription but responsive to environmental cues. Our studies with the chromatin remodeler Mi-2¿ in keratinocytes provide strong support for this hypothesis. Mi-2¿ has a very specific and central role in guarding against the inappropriate activation of a keratinocyte's stress response and repair functions by maintaining genes in these pathways in a repressed state. Among the Mi-2¿ targets is TSLP, best known as a "pro-inflammatory signal " in other contexts, which in contrast plays a key protective role to resolve an epigenetically induced stress response that occurs when Mi-2¿ function is blocked. The role of Mi-2¿ and TSLP in keratinocyte homeostasis is investigated by three specific aims. In the first aim, we establish the genes regulated by Mi-2¿ in wild type keratinocytes, as well as the network of transcription factors and epigenetic regulators that contribute to Mi-2¿'s regulation of the stress- response gene signature. In the second aim, we further evaluate the hypothesis that Mi-2¿ functions by establishing a local chromatin environment that influences the recruitment or activity of transcription regulators at pro- inflammatory genes, such as TSLP. In third aim, we address the role of TSLP, a select Mi-2¿ target, as a protective factor in stress-mediated skin pro-inflammatory responses. Taken together our studies seek to establish the regulatory nexus that connects the epigenetic, transcriptional and cellular mechanisms supporting keratinocyte homeostasis and stress responses