Transcriptional Co-regulators in Epidermis

描述（由申请人提供）：我们研究项目的长期目标是了解表皮发育和表皮内分化的转录控制。表皮的一个关键功能是形成有效的渗透性屏障；表皮屏障缺陷导致许多皮肤病。屏障的形成与表皮角质形成细胞的最终分化有着复杂的联系，它取决于表皮颗粒层中的结构蛋白、蛋白酶、脂质组成和细胞-细胞粘附。虽然我们已经对屏障的细胞生物学有了重要的了解，但对控制其形成的机制知之甚少。特别是，我们不太了解编码屏障成分的多个基因协调表达的转录控制。在该奖项的最后一个资助期，我们基于与limi -only因子LMO4的相互作用发现了Grainyhead-like transcription factor Grainyhead-like Epithelial Transactivator 1 （Get1/Grhl3）。在发育过程中，Get1和LMO4都在发育中的表皮中表达，这表明它们在表皮形成中起作用。Get1基因的缺失导致与表皮终末分化和屏障形成相关的多个基因的表达改变。此外，同时缺失Get1和LMO4会导致更严重的终端分化缺陷，这表明我们已经确定了控制终端分化和屏障形成的关键转录因子。基于这些发现，我们假设Get1以特定阶段的方式直接调节多个终末分化基因，并且Get1与LMO4形成复合物来调节这些基因的至少一个子集。在这项更新申请中，我们提出了三个具体目标：1)确定Get1敲除小鼠中多个终端分化基因解除调控的机制；2)确定Get1调控表皮终末分化的时间要求；3)确定Get1和LMO4是否参与调控表皮终末分化的复合体。这些研究将增强我们对表皮屏障形成缺陷的理解，并可能有助于发现治疗方案。皮肤屏障缺陷是一个重大的公共卫生问题，发生在几种遗传性和获得性皮肤疾病中，也发生在早产儿中。

DESCRIPTION (provided by applicant): The long-term objective of our research program is to understand transcriptional control of epidermal development and differentiation within the epidermis. One critical function of the epidermis is to form an effective permeability barrier; defective epidermal barrier contributes to many skin diseases. The formation of the barrier, which is intricately linked to the terminal differentiation of epidermal keratinocytes, depends on structural proteins, proteases, lipid composition and cell-cell adhesion in the granular layer of the epidermis. While we have gained significant understanding of the cell biology of the barrier, much less is known about the mechanisms that control its formation. In particular, we do not understand well the transcriptional control that underlies the coordinated expression multiple genes encoding barrier components. In the last funding period of this award, we discovered the Grainyhead-like transcription factor Grainyhead-like Epithelial Transactivator 1 (Get1/Grhl3) based on its interaction with the LIM-only factor LMO4. During development, both Get1 and LMO4 are expressed in the developing epidermis, suggesting a role in epidermal formation. Deletion of the Get1 gene leads to alterations in the expression of multiple genes linked to terminal differentiation and barrier formation of the epidermis. Furthermore, simultaneous deletion of both Get1 and LMO4 leads to a more severe defect in terminal differentiation, indicating that we have identified key transcription factors for control of terminal differentiation and barrier formation. Based on these findings we hypothesize that Get1 directly regulates multiple terminal differentiation genes in a stage-specific manner, and that Get1 forms a complex with LMO4 to regulate at least a subset of these genes. In this renewal application, we propose three Specific Aims: 1) to determine the mechanisms underlying deregulation of multiple terminal differentiation genes in Get1 knockout mice; 2) to define the temporal requirement for Get1 in regulation of epidermal terminal differentiation; and 3) to determine whether Get1 and LMO4 act in a complex to regulate terminal differentiation of the epidermis. These investigations will enhance our understanding of defective epidermal barrier formation, and may aid the discovery of treatment options. Defective skin barrier is a significant public health problem that occurs in several inherited and acquired diseases of the skin, as well as in premature infants.