Epigenetic regulation of proinflammatory responses in the skin

摘要 我们已经证明，基底层表皮中染色质重构体Mi-2β的丢失是导致 在缺乏任何致炎和应激反应基因的情况下快速上调 明显的环境信号或皮肤屏障缺陷。这些数据支持这样的假设 免疫细胞调节基因，通常由环境侮辱在表皮中诱导， 在表皮条件下，直接和主动地受到染色质调节剂的抑制 动态平衡。我们现在建议研究基于染色质的机制，通过它 免疫调节基因在角质形成细胞中保持稳定表达，并确定 机械或环境伤害激活的信号通路如何逆转这些 机械装置。 第一个目标，我们将建立“消炎”染色质景观和 控制角质形成细胞动态平衡的转录因子网络。全基因组 将在角质形成细胞中使用这些方法来建立直接 并由Mi-2β进行功能控制。Mi-2β关联的调节元件的类型 它们所处的染色质构型将被建立。序列- 功能上以协同或拮抗方式相互作用的特定DNA结合因子 随着米-2的出现，β将被识别出来。最后，染色质调节剂和转录的谱系 以Mi-2β−独立方式参与促炎基因调控的因子将是 也是成立的。 在第二个目标中，我们将确定环境信号是如何诱导亲本的。 角质形成细胞中炎性基因的表达。环境信号对生物多样性的影响 改变染色质调节因子和转录因子的活性将被研究。 我们将首先研究Mi-2β与表观遗传和 转录因子在其目标基因的调节域上组成。然后我们将测试 环境信号如何通过改变Mi-2的活性诱导促炎基因 2β及其相关的染色质调节因子和转录因子。钥匙的作用 这一分子过程中的调控候选者将由Genetic进一步评估 对小鼠和人类角质形成细胞的干扰研究。 这些研究的结果将使我们能够探讨保守的机制 在促炎的基础上促进人类皮肤病，并提供新的途径 进行治疗干预。

ABSTRACT We have shown that loss of the chromatin remodeler Mi-2β in the basal epidermis causes rapid up-regulation of pro-inflammatory and stress response genes in the absence of any overt environmental signals or a skin barrier defect. These data support the hypothesis that immune cell regulatory genes, normally induced in the epidermis by environmental insults, are directly and actively repressed by chromatin regulators, under conditions of epidermal homeostasis. We now propose to study the chromatin-based mechanisms by which immune-regulatory genes are kept poised for expression in keratinocytes and to determine how activation of signaling pathways by mechanical or environmental insult reverses these mechanisms. In the first aim, we will establish the “anti-inflammatory” chromatin landscape and transcription factor network that control keratinocyte homeostasis. Genome-wide approaches will be used in keratinocytes to establish the gene networks that are directly and functionally controlled by Mi-2β. The types of regulatory elements that Mi-2β associates with, and the chromatin configuration that they are in will be established. The sequence- specific DNA binding factors that functionally interact in a synergistic or antagonistic fashion with Mi-2β will be identified. Finally, the repertoire of chromatin regulators and transcription factors involved in pro-inflammatory gene regulation in a Mi-2β−independent fashion will be also established. In the second aim, we will determine how environmental signals induce pro- inflammatory gene expression in keratinocytes. The effect of environmental signals on altering the activity of both chromatin regulators and transcription factors will be studied. We will first examine the cause-effect relationship between Mi-2β and the epigenetic and transcription factor makeup at the regulatory domains of its target genes. We will then test how environmental signals induce pro-inflammatory genes by altering the activities of Mi- 2β and associated chromatin regulators and transcription factors. The role of key regulatory candidates in this molecular process will be further evaluated by genetic interference studies in mouse and human keratinocytes. The outcome of these studies will allow us to probe into conserved mechanisms that contribute to human skin disease with a pro-inflammatory basis and provide new avenues for therapeutic intervention.