Epigenetic regulation of epidermal homeostasis

表皮稳态的表观遗传调控

• 批准号: 8584899
• 负责人: KATIA GEORGOPOULOS
• 金额: $ 33.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-25 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8584899
• 关键词: Ablation; Address; Adult; Agonist; Antigens; Atopic Dermatitis; Binding; Binding Sites; Cells; Chromatin; Complex; Cues; DNA; DNA Binding; Dependence; Disease; Embryo; Environment; Epigenetic Process; Epithelial Cells; Gap Junctions; Gene Targeting; Genes; Genetic; Genetic Transcription; Health; Homeostasis; Immune; Immune response; Inflammatory; Inflammatory Response; Interruption; Maintenance; Mediating; Modeling; Molecular; Molecular Models; Mutant Strains Mice; Mutation; Nuclear Receptors; Pathway interactions; Play; Process; RXR; Regulation; Role; Signal Transduction; Site; Skin; Stress; TSLP gene; Testing; Therapeutic; Trauma; Vitamin D3 Receptor; Work; arm; base; biological adaptation to stress; cell type; chemokine; chromatin remodeling; cytokine; design; effective therapy; genome-wide; histone modification; keratinocyte; molecular modeling; mutant; prevent; repaired; response; skin disorder; therapeutic target; transcription factor

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

描述(申请人提供)：皮肤中的角质形成细胞准备通过激活增殖修复反应和刺激常驻免疫细胞发起炎症反应来应对环境侮辱。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的抗原介导的。参与这一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保持在表观遗传状态，该状态准备转录，但对环境提示有反应。我们对角质形成细胞中染色质重构体Mi-2的研究有力地支持了这一假说。MI-2通过保持这些通路中的基因处于抑制状态，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发挥着非常特定和核心的作用。TSLP是Mi-2？靶标之一，在其他情况下被称为“促炎信号”，相反，它在解决当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。Mi-2？和TSLP在角质形成细胞动态平衡中的作用有三个特定的目的。在第一个目标中，我们建立了受Mi-2？in调控的基因 野生型角质形成细胞，以及转录因子网络和表观遗传调节因子网络，有助于Mi-2‘S对应激反应基因信号的调控。在第二个目标中，我们进一步评估了Mi-2通过建立一个局部染色质环境来影响促炎基因(如TSLP)转录调节因子的招募或活性而发挥作用的假设。在第三个目标中，我们讨论了TSLP的作用，TSLP是一个精选的Mi-2？靶点，在应激介导的皮肤促炎反应中作为保护因子。综上所述，我们的研究试图建立起将支持角质形成细胞动态平衡和应激反应的表观遗传、转录和细胞机制联系起来的调节关系。