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

描述(申请人提供)：不同的染色质重塑复合体在染色质状态和癌症中的作用虽然体内的所有细胞都含有相同的DNA，但表达模式的变化导致了细胞类型的巨大多样性。这一过程的一种调节方式是通过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。这种分子的包装有多紧密可能会对基因表达产生深远的影响。一种名为染色质重塑复合体的蛋白质家族能够改变染色质结构，从而允许基因的开启或关闭。对许多肿瘤类型的大规模测序研究已经确定了染色质重塑复合体中的大量突变。由于染色质重塑复合体的突变在许多类型的癌症中都很常见，了解当其中一个复合体丢失时基因表达和染色质结构的变化可能有助于开发许多癌症也常见的治疗策略。染色质重塑复合体有四个家族，它们都承担着改变染色质结构的共同职责。最近有人提出，重塑蛋白家族之间以及与其他染色质调节蛋白之间存在显著的相互作用。这项建议的主要目标是确定一种类型的染色质重塑复合体的缺失如何影响染色质的全球状态，以及这些变化可能如何推动细胞走向癌症。染色质重构体的SWI/SNF家族有许多变异形式，其中几个变异在肝细胞癌中很常见。利用这个模型系统，上述问题将分三个部分得到解决：1)不同形式的SWI/SNF染色质重塑复合体在基因组中的作用是什么？当该复合体的变异形式丢失时，基因表达和染色质结构会发生什么？当这种复合体丢失时，小鼠的肝脏会发生什么变化，丢失会导致肿瘤的形成吗？SWI/SNF复合体最初是作为一个单一的实体进行研究的，但该复合体几个相互排斥的亚基的频繁突变突显了更好地了解该复合体的许多变体形式的必要性。这个项目的成功完成将产生关键的见解，即不同形式的改建综合体是否都以相同的方式发挥作用，或者更确切地说，这些综合体是否具有更复杂的相互作用。了解这一区别对于设计针对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.