Transcriptional memory and insulator function at Drosophila even skipped

描述(申请人提供)：基因转录的变化在癌症、大多数其他人类疾病的进展、衰老过程以及多细胞生物体的所有阶段的发育中都是重要的。详细了解这些变化是如何被调控的，是诊断工具和干预策略的基础。进一步的进步意味着新方法的前景，以及现有方法的有效性提高。重要的是，关于所涉及的基本过程仍有许多问题。果蝇体内可用的工具使我们有可能在真实的活体环境中详细研究作用和相互作用的机制。这项建议是为了研究基于染色质的基因调控机制，涉及多梳反应元件和绝缘体，最近发现在特征明确的果蝇基因中甚至跳过。这些研究将解决核内转录记忆和染色体组织如何在3个维度上发挥作用的基本问题。它们将提供对表观遗传机制如何传播可选转录状态的更清晰的理解，以及远距离基因组区域之间远程调控相互作用的重要性。在哺乳动物中，多梳组蛋白参与干细胞生态位的维持和肿瘤的发生。因此，这些研究将直接应用于人类疾病的研究。其具体目的是：1)研究偶跳过多梳反应元件维持抑制和激活的机制；2)研究绝缘子介导的远程增强子-启动子通信机制；3)测试偶跳过多梳反应元件和绝缘子在其自然环境中的性质和功能。 公共卫生相关性：基因转录的变化在癌症、大多数其他人类疾病的进展、衰老过程以及所有阶段的多细胞生物体的发育过程中都是重要的。详细了解这些变化是如何被监管的，是诊断工具和干预策略的基础，也是本提案的总体主题。进一步的进步意味着新方法的前景，以及现有方法的有效性提高。

DESCRIPTION (provided by applicant): Changes in gene transcription are important in the progression of cancer, in most other human diseases, and in the aging process, as well as in the development of multicellular organisms at all stages. A detailed understanding of how such changes are regulated is the basis of both diagnostic tools and intervention strategies. Further advancement holds the promise of novel approaches, and of increased effectiveness of current approaches. Importantly, many questions remain about the fundamental processes involved. Tools available in Drosophila make it possible to study mechanisms of action and interaction in detail, in a true in vivo context. This proposal is to study mechanisms of chromatin-based gene regulation involving Polycomb- response elements and an insulator, recently discovered in the well-characterized Drosophila gene even skipped. These studies will address basic questions of how transcriptional memory and chromosome organization work in 3 dimensions in the nucleus. They will provide a clearer understanding of how epigenetic mechanisms propagate alternative transcriptional states, and the importance of long-range regulatory interactions between distant genomic regions. In mammals, Polycomb Group proteins are involved in maintenance of the stem cell niche, and in oncogenesis. Therefore, these studies will have direct applications to research on human diseases. The Specific Aims are: 1) to investigate mechanisms of maintenance of repression and activation by Polycomb- response elements from the even-skipped locus 2) to study mechanisms of long-range insulator-mediated enhancer-promoter communication, and 3) to test the properties and functions of even-skipped Polycomb-response elements and the insulator in their native context. PUBLIC HEALTH RELEVANCE: Changes in gene transcription are important in the progression of cancer, in most other human diseases, and in the aging process, as well as in the development of multicellular organisms at all stages. A detailed understanding of how such changes are regulated is the basis of both diagnostic tools and intervention strategies, and is the general subject of this proposal. Further advancement holds the promise of novel approaches, and of increased effectiveness of current approaches.