Xist-mediated nucleation of heterochromatin and (epi)genetic stability of the inactive X chromosome

Xist 介导的异染色质成核和失活 X 染色体的（表观）遗传稳定性

• 批准号: 187885059
• 负责人: Dr. Stefan Pinter
• 金额: --
• 依托单位: Department of Molecular Biology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/187885059?language=en
• 关键词: Xist; mediated; nucleation; heterochromatin; epi

Human cancer is a complex disease triggered by a combination of oncogene activation and tumor suppressor gene inactivation, changes that are increasingly attributed not only to genetic but also epigenetic instability. Numerous clinical trials for a new generation of drugs targeting chromatin modifying complexes are underway and existing "epigenetic drugs" such as DNA methylation or histone deacetylation inhibitors are adopted for a wider selection of cancer types. Since the therapeutic benefit of reactivating a tumor suppressor in cancer cells is compromised if previously untransformed cells acquire a tumorigenic epigenetic program, the stability of the untransformed epigenetic state during treatment is of paramount importance.The inactive X chromosome (Xi) in female mammals is a classic example of epigenetics and can serve as a useful paradigm towards understanding the molecular mechanisms that determine the stability of euchromatin and heterochromatin. This proposal uses massively parallel sequencing technology, custom bioinformatics and mouse genetics to address three major questions in the field: 1.) How are inactivating chromatin marks spread over the chromosome when the future Xi is established? 2.) What role do specific DNA sequences play in establishing and maintaining the inactive state of the Xi? 3.) How does the loss of Xist RNA, the critical factor in Xi establishment, impact the genetic and epigenetic stability of the Xi in the maintenance phase? The answers to these questions will provide basic insights into how Xi heterochromatin is organized, test whether repetitive elements shape Xi chromatin, and may help to identify novel X-linked oncogenes.

人类癌症是由癌基因激活和肿瘤抑制基因失活的组合触发的复杂疾病，这些变化越来越多地不仅归因于遗传不稳定性，而且归因于表观遗传不稳定性。许多针对染色质修饰复合物的新一代药物的临床试验正在进行中，现有的“表观遗传药物”如DNA甲基化或组蛋白脱乙酰化抑制剂被用于更广泛的癌症类型选择。由于如果先前未转化的细胞获得致瘤性表观遗传程序，则重新激活癌细胞中的肿瘤抑制因子的治疗益处会受到损害，治疗期间未转化的表观遗传状态的稳定性是至关重要的。是表观遗传学的一个经典例子，可以作为一个有用的范例，了解决定稳定性的分子机制。常染色质和异染色质。该提案使用大规模并行测序技术，定制生物信息学和小鼠遗传学来解决该领域的三个主要问题：1。当未来的Xi被建立时，失活染色质标记是如何遍布染色体的？2.）的情况。特定的DNA序列在建立和维持Xi的非活动状态中扮演什么角色？3.）第三章Xist RNA的丢失是Xi建立的关键因素，它如何影响Xi在维持阶段的遗传和表观遗传稳定性？这些问题的答案将提供关于Xi异染色质如何组织的基本见解，测试重复元件是否塑造Xi染色质，并可能有助于识别新的X连锁癌基因。