The Role of Variant Chromatin Remodeling Complexes on Chromatin State and Cancer

描述（由申请人提供）：变异染色质重塑复合物在染色质状态和癌症中的作用尽管体内所有细胞都含有相同的DNA，但表达模式的变化导致细胞类型的巨大多样性。调节这一过程的一种方式是通过DNA的物理结构。在细胞中，DNA包裹在称为组蛋白的蛋白质周围形成染色质。这种分子的紧密包装程度对基因表达有着深远的影响。一个被称为染色质重塑复合物的蛋白质家族能够改变染色质结构，允许基因打开或关闭。许多肿瘤类型的大型测序研究已经确定了染色质重塑复合物中的许多突变。由于染色质重塑复合物中的突变在许多类型的癌症中很常见，因此了解这些复合物中的一种丢失时发生的基因表达和染色质结构的变化可能会为许多癌症的治疗策略的发展提供见解。 染色质重塑复合物有四个家族，它们都执行改变染色质结构的共同任务。最近有人提出，重塑蛋白家族之间存在显著的相互作用，以及与其他染色质调节蛋白的相互作用。该提案的主要目标是确定一种类型的染色质重塑复合物的丢失如何影响染色质的整体状态，以及这些变化如何驱动细胞走向癌症。染色质重塑的SWI/SNF家族具有许多变体形式，并且这些变体中的几个在肝细胞癌中通常发生突变。使用该模型系统，上述问题将分三部分解决：1. SWI/SNF染色质重塑复合物的变体形式在基因组中的何处起作用？2.）的情况。当这种复合物的变体形式丢失时，基因表达和染色质结构会发生什么变化？3.）第三章当这种复合物丢失时，小鼠肝脏会发生什么变化，丢失会导致肿瘤形成吗？ SWI/SNF复合物主要作为单一实体进行研究，但该复合物的几个相互排斥的亚基中的频繁突变突出了更好地理解该复合物的许多变体形式的需要。这个项目的成功完成将产生重要的见解，无论是重塑复合物的变体形式都以相同的方式发挥作用，或者更确切地说，如果这些复合物具有更复杂的相互作用。理解这种区别对于设计靶向肿瘤细胞染色质状态的治疗策略至关重要。

DESCRIPTION (provided by applicant): The Role of Variant Chromatin Remodeling Complexes in Chromatin State and Cancer Although all cells in the body contain the same DNA, variations in the patterns of expression give rise to a huge diversity of cell types. One way this process is regulated is by the physical structure of DNA. In cells, DNA is wrapped around proteins called histones to form chromatin. How tightly packaged this molecule is can have profound effects on gene expression. A family of proteins called chromatin remodeling complexes are capable of altering chromatin structure, allowing genes to be turned on or off. Large sequencing studies of many tumor types has identified numerous mutations in chromatin remodeling complexes. Because mutations in chromatin remodeling complexes are common in many types of cancer, understanding the changes in gene expression and chromatin structure that occur when one of these complexes is lost may provide insight towards the development of therapeutic strategies also common to many cancers. There are four families of chromatin remodeling complexes, and all perform the common duty of altering chromatin structure. It has recently been proposed that there is significant interactions between families of remodeling proteins, as well as interactions with other chromatin regulating proteins. The main goal of this proposal is to determine how loss of one type of chromatin remodeling complex affects the global state of chromatin and how these changes may drive a cell towards cancer. The SWI/SNF family of chromatin remodeler has many variant forms, and several of these variants are commonly mutated in hepatocellular carcinoma. Using this model system the above question will be addressed in three parts: 1.) Where do variant forms of the SWI/SNF chromatin remodeling complex function in the genome? 2.) What happens to gene expression and chromatin structure when a variant form of this complex is lost? 3.) What changes occur in the mouse liver when this complex is lost, and does loss lead to tumor formation? The SWI/SNF complex has primarily been studied as a single entity, but frequent mutations in several mutually exclusive subunits of this complex highlight the need for a better understanding of the many variant forms of the complex. Successful completion of this project will yield critical insights ino whether variant forms of a remodeling complex all function in the same way, or rather, if these complexes have more complicated interactions. Understanding this distinction will be critical for designing therapeutic strategies that target the chromatin state of a tumor cell.