Polycomb genes and keratinocyte function

描述（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控因子。尽管认识到这一点，但尚未考虑到它们可能发挥维持表皮角质形成细胞存活的作用。这可能是因为这个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被认识到。我们的初步研究表明，Bmi-1存在于表皮，升高的Bmi-1促进角质细胞增殖和存活。我们还发现，Bmi-1在牛皮癣和癌症等疾病中升高，这表明它在这些疾病的发生中起着重要作用。我们已经建立了一种动物模型，该模型对Bmi-1产生增厚的增生性表皮反应，这一发现表明Bmi-1在表皮生理学中具有功能作用。特异性Aim 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依赖性天花素基因表达抑制相关的染色质修饰事件。特异性Aim 2旨在表征Bmi-1的抗凋亡作用。特异性Aim 3将确定在细胞凋亡、细胞增殖和基因表达的生理变化中负责的Bmi-1结构域。特异性Aim 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剂在体内的作用。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。描述：Bmi-1 Polycomb Group （PcG）基因是一种重要的表观遗传调控因子，可增强干细胞的存活。然而，它在表皮中的作用尚未被研究。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基因在组织中的作用的经典教条。

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.