Polycomb genes and keratinocyte function

描述(由申请人提供)：摘要BMI-1和其他聚梳组(PcG)基因是细胞存活的重要表观遗传调节因子。尽管认识到了这一点，但它们可能在维持表皮角质形成细胞存活方面发挥作用的可能性尚未被考虑。这很可能是因为这一领域现在处于发现的前沿，因为这些蛋白质的重要性直到最近才得到重视。我们的初步研究表明，Bmi-1存在于表皮中，升高的Bmi-1促进角质形成细胞的增殖和存活。我们还表明，BMI-1在牛皮癣和癌症等疾病中升高，表明在这些疾病的发生中发挥了作用。我们已经建立了一个动物模型，对BMI-1做出反应，形成增厚的过度增殖的表皮--这一发现表明在表皮生理学中具有功能作用。具体目的1旨在评估BMI-1对表皮角质形成细胞增殖和存活的影响，并研究与BMI-1依赖抑制总蛋白基因表达相关的染色质修饰事件。特异靶2是为了研究BMI-1的抗细胞凋亡作用。特异靶3将识别Bmi-1结构域(S)，这些结构域负责细胞凋亡、细胞增殖和基因表达的生理变化。特定目的4利用在表皮表达BMI-1的转基因小鼠来评估这种表观遗传调节因子在体内的作用。我们相信，这些研究具有创新性和“高影响力”，因为它们将改变关于BMI-1和其他PcG基因在组织中的作用的经典教条。简介：BMI-1 Polycomb Group(PcG)基因是一种重要的表观遗传调节因子，可提高干细胞的存活率。然而，对表皮的作用还没有被研究过。我们发现BMI-1在小鼠表皮中表达，促进细胞周期进程，抑制细胞凋亡，具有非干细胞功能，驱动小鼠表皮的过度增殖，可能参与了增生性皮肤病的发生。这些研究认为，BMI-1在表皮中具有重要的生理作用。这些研究具有创新性和“高影响力”，因为它们将改变关于PcG基因在组织中作用的经典教条。

DESCRIPTION (provided by applicant): Abstract Bmi-1 and the other Polycomb Group (PcG) genes are important epigenetic regulators of cell survival. In spite of this realization the possibility that they may play a role maintaining epidermal keratinocyte survival has not been considered. This is likely because this area is now at the forefront of discovery since the importance of these proteins was only recently appreciated. Our preliminary studies show that Bmi-1 is present in epidermis and that elevated Bmi-1 promotes keratinocyte proliferation and survival. We also show that Bmi-1 is elevated in diseases such as psoriasis and cancer, suggesting a role in the genesis of these disorders. We have created an animal model that develops a thickened hyperproliferative epidermis in response to Bmi-1 - a finding that suggests a functional role in epidermal physiology. Specific Aim 1 is designed to assess the impact of Bmi-1 in epidermal keratinocyte proliferation and survival and to study the chromatin modification events associated with Bmi-1 dependent suppression of involucrin gene expression. Specific Aim 2 is designed to characterize the anti-apoptosis effect of Bmi-1. Specific Aim 3 will identify Bmi-1 domain(s) that are responsible for the physiological changes in apoptosis, cell proliferation and gene expression. Specific Aim 4 utilizes transgenic mice which express Bmi-1 in epidermis to assess the in vivo role of this epigenetic regulator. We believe that these studies are innovative and "high impact" because they will change the classical dogma regarding the role of Bmi-1 and other PcG genes in tissues. NARRATIVE: The Bmi-1 Polycomb Group (PcG) gene is an important epigenetic regulator that enhances stem cell survival. However, a role in epidermis has not been studied. We show that Bmi-1 is expressed in epidermis, promotes cell cycle progression, inhibits apoptosis, has non-stem cell functions, drives hyperproliferation in mouse epidermis, and is likely to be involved in the genesis of hyperproliferative skin disease. These studies argue that Bmi-1 has a physiologically important role in epidermis. These studies are innovative and "high impact" because they will change the classical dogma regarding the role of PcG genes in tissues.