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以及刺激常驻免疫细胞以启动炎症反应而对环境损伤做出反应。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意味着它们在角质形成细胞中维持在表观遗传状态，该状态准备转录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 <$的研究为这一假设提供了强有力的支持。Mi-2在防止角质形成细胞的应激反应和修复功能的不适当激活方面具有非常特异和核心的作用，通过将这些途径中的基因维持在受抑制的状态。在Mi-2中，靶点是TSLP，在其他情况下最为人所知的是“促炎信号“，相比之下，TSLP在解决Mi-2功能被阻断时发生的表观遗传诱导的应激反应方面起着关键的保护作用。通过三个具体目标研究Mi-2 <$和TSLP在角质形成细胞稳态中的作用。在第一个目标中，我们建立了Mi-2调节的基因， 野生型角质形成细胞，以及转录因子和表观遗传调节因子的网络，有助于Mi-2调节应激反应基因签名。在第二个目标中，我们进一步评估了Mi-2？通过建立局部染色质环境来发挥作用的假设，该染色质环境影响促炎基因（如TSLP）的转录调节因子的募集或活性。在第三个目标中，我们解决了TSLP的作用，一个选择Mi-2的目标，作为应激介导的皮肤促炎反应中的保护因子。总之，我们的研究试图建立连接支持角质形成细胞稳态和应激反应的表观遗传、转录和细胞机制的调控关系

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