Hox gene regulation by the Snf5 tumor suppressor

描述(申请人提供)：几十年来，HOX簇的基因一直吸引着科学家的兴趣，因为它们在构建身体计划模式中的作用，它们的物理接近，以及它们被称为共线性的顺序基因表达的现象。最近的研究表明，染色质结构的动态调节在这些基因的调控中起着不可或缺的作用。例如，多梳复合体甲基化H3K27以抑制Hox的表达，而MLL和Trithorax甲基化H3K4以激活转录。依赖于三磷酸腺苷的染色质重塑复合体在控制HOX基因表达中的作用还知之甚少。这些复合体通过利用三磷酸腺苷来调节核小体位置来重塑染色质。一些证据表明，Swi/SNF染色质重塑复合体在HOX基因的调控中起着不可或缺的作用。果蝇Brahma是一种ATPase，也是Swi/SNF复合体的核心成分，它是从调节Hox基因表达的因子的筛选中反复分离出来的。最近，我们发现SWI/SNF复合体的另一个核心成分Snf5是HOX基因在小鼠胚胎成纤维细胞中表达所必需的。最后，多个研究小组已经证明，Snf5与MLL及其果蝇同源三胸之间存在物理上的相互作用，这两个基因都正向调节HOX基因的表达。有趣的是，MLL易位经常在急性白血病中发现，Snf5的失活突变会导致儿童侵袭性癌症，并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是导致多种类型癌症的原因之一。这项建议中的实验将检验这样的假设，即Snf5在集群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的相互作用而促进的。通过阐明Snf5在MLL介导的HOx基因激活中的作用以及Snf5调控HOx基因的机制基础，这些实验结果将揭示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在人类癌症中都有突变，深入了解它们在基因调控和转化中的作用可能会为这些致命癌症的治疗干预找到新的靶点。

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.