Transcriptional memory and insulator function at Drosophila even skipped

描述（由申请人提供）：基因转录的变化在癌症的进展、大多数其他人类疾病和衰老过程中以及在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调节的是诊断工具和干预战略的基础。进一步的进步有望产生新的方法，并提高当前方法的有效性。重要的是，关于所涉及的基本过程仍然存在许多问题。在果蝇中可用的工具使得在真实的体内环境中详细研究作用和相互作用的机制成为可能。这项建议是研究基于染色质的基因调控机制，涉及Polycomb反应元件和绝缘体，最近发现的特点是果蝇基因甚至跳过。这些研究将解决转录记忆和染色体组织如何在细胞核中三维工作的基本问题。他们将提供一个更清晰的理解表观遗传机制如何传播替代转录状态，以及远程调控之间的相互作用的重要性遥远的基因组区域。在哺乳动物中，Polycomb Group蛋白参与干细胞生态位的维持和肿瘤发生。因此，这些研究将直接应用于人类疾病的研究。 具体目标是：1）研究来自偶数跳过基因座的Polycomb反应元件的抑制和激活的维持机制2）研究长距离绝缘子介导的增强子-启动子通讯的机制，和3）测试偶数跳过Polycomb反应元件和绝缘子在其天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的进展中是重要的，在大多数其他人类疾病中，在衰老过程中，以及在多细胞生物体发育的各个阶段。详细了解这些变化是如何调节的，是诊断工具和干预战略的基础，也是本提案的一般主题。进一步的进步有望产生新的方法，并提高当前方法的有效性。

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.