Polycomb genes and keratinocyte function

描述（由申请人提供）：摘要Bmi-1和其他Polycomb Group（PcG）基因是细胞存活的重要表观遗传调节因子。尽管认识到这一点，但尚未考虑它们可能在维持表皮角质形成细胞存活中发挥作用的可能性。这可能是因为这个领域现在处于发现的最前沿，因为这些蛋白质的重要性最近才被认识到。我们的初步研究表明，Bmi-1存在于表皮中，并且升高的Bmi-1促进角质形成细胞增殖和存活。我们还表明，Bmi-1在银屑病和癌症等疾病中升高，表明在这些疾病的发生中起作用。我们已经建立了一个动物模型，该模型对Bmi-1产生反应，产生增厚的过度增殖表皮-这一发现表明表皮生理学中的功能性作用。具体目标1旨在评估Bmi-1在表皮角质形成细胞增殖和存活中的影响，并研究与Bmi-1依赖性抑制外皮蛋白基因表达相关的染色质修饰事件。具体目标2旨在表征Bmi-1的抗凋亡作用。具体目标3将鉴定负责细胞凋亡、细胞增殖和基因表达中的生理变化的Bmi-1结构域。具体目标4利用在表皮中表达Bmi-1的转基因小鼠来评估这种表观遗传调节剂的体内作用。我们相信这些研究是创新的和“高影响力”的，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。Bmi-1 Polycomb Group（PcG）基因是一种重要的表观遗传调节因子，可增强干细胞存活。然而，在表皮中的作用尚未研究。我们发现Bmi-1在表皮中表达，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，并且可能参与过度增殖性皮肤病的发生。这些研究表明，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.