Hox gene regulation by the Snf5 tumor suppressor

Snf5 肿瘤抑制因子对 Hox 基因的调控

• 批准号: 7409828
• 负责人: Eva Lorena Mora-Blanco
• 金额: $ 3.17万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7409828
• 关键词: ATP phosphohydrolase; Acute leukemia; Body Patterning; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Complex; Coupled; Data; Drosophila genus; Embryo; Fibroblasts; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Hereditary Malignant Neoplasm; Homologous Gene; Human; Lead; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Mus; Mutate; Mutation; Nucleosomes; Play; Polycomb; Positioning Attribute; Reagent; Regulation; Role; Scientist; Syndrome; Testing; Therapeutic Intervention; Thinking; Tumor Suppressor Proteins; Work; base; brahma; cancer type; insight; novel; research study

DESCRIPTION (provided by applicant): The genes of the Hox clusters have intrigued scientists for decades due to their role in patterning the body plan, their physical proximity and the phenomenon of their sequential gene expression known as colinearity. Recent work has shown that dynamic modulation of chromatin structure plays an indispensable role in the regulation of these genes. For instance, Polycomb complexes methylate H3 K27 to repress Hox expression while MLL and Trithorax methylate H3 K4 to activate transcription. The roles of ATP dependent chromatin remodeling complexes in controlling Hox gene expression are less understood. These complexes remodel chromatin by utilizing ATP to modulate nucleosome position. Several lines of evidence suggest that the Swi/Snf chromatin-remodeling complex plays an integral role in regulation of Hox genes. Drosophila Brahma, an ATPase and core component of the Swi/Snf complex, was repeatedly isolated from a screen for factors that regulate Hox gene expression. Recently, we have found Snf5, another core component of the Swi/Snf complex, is specifically required for Hox gene expression in murine embryonic fibroblasts. Lastly, multiple groups have shown that Snf5 physically interacts with MLL and its Drosophila homolog Trithorax, both of which positively regulate Hox gene expression. Intriguingly, translocations of MLL are frequently found in acute leukemias and inactivating mutations of Snf5 lead to aggressive pediatric cancers and are the basis of a familial cancer syndrome. In fact, dysregulation of Hox gene expression is thought to contribute to the genesis of numerous types of cancer. The experiments in this proposal will test the hypothesis that Snf5 plays a critical role in the regulation of clustered Hox gene expression and that this regulation is facilitated by interactions with MLL. By elucidating the role of Snf5 in MLL-mediated activation of Hox genes and by identifying the mechanistic basis of Hox gene regulation by Snf5, the results of these experiments will delineate the role of Swi/Snf in Hox gene expression and will provide a framework for understanding the chromatin-based regulation of gene expression. Since MLL and Snf5 are both mutated in human cancers, generating insight into their roles in gene regulation and transformation may identify novel targets for therapeutic intervention to these lethal cancers.

描述（由申请人提供）：Hox 簇的基因几十年来一直引起科学家们的兴趣，因为它们在塑造身体计划中的作用、它们的物理接近性以及被称为共线性的顺序基因表达现象。最近的工作表明，染色质结构的动态调节在这些基因的调节中起着不可或缺的作用。例如，Polycomb 复合物甲基化 H3 K27 以抑制 Hox 表达，而 MLL 和 Trithorax 甲基化 H3 K4 以激活转录。 ATP 依赖性染色质重塑复合物在控制 Hox 基因表达中的作用尚不清楚。这些复合物通过利用 ATP 调节核小体位置来重塑染色质。多项证据表明，Swi/Snf 染色质重塑复合物在 Hox 基因的调节中发挥着不可或缺的作用。果蝇 Brahma 是一种 ATP 酶，也是 Swi/Snf 复合物的核心成分，在筛选调节 Hox 基因表达的因子时被反复分离出来。最近，我们发现Swi/Snf复合物的另一个核心成分Snf5是小鼠胚胎成纤维细胞中Hox基因表达所特别需要的。最后，多个研究小组表明，Snf5 与 MLL 及其果蝇同源物 Trithorax 存在物理相互作用，两者均能正向调节 Hox 基因表达。有趣的是，MLL 易位经常在急性白血病中发现，而 Snf5 的失活突变会导致侵袭性儿科癌症，并且是家族性癌症综合征的基础。事实上，Hox 基因表达失调被认为导致多种癌症的发生。本提案中的实验将检验以下假设：Snf5 在簇状 Hox 基因表达的调节中发挥关键作用，并且这种调节是通过与 MLL 的相互作用来促进的。通过阐明Snf5在MLL介导的Hox基因激活中的作用，并确定Snf5调节Hox基因的机制基础，这些实验的结果将描述Swi/Snf在Hox基因表达中的作用，并将为理解基于染色质的基因表达调控提供一个框架。由于 MLL 和 Snf5 在人类癌症中均发生突变，深入了解它们在基因调控和转化中的作用可能会确定对这些致命癌症进行治疗干预的新靶点。