Discovering the function of distinct SWI/SNF complexes

SWI/SNF复合物家族是染色质重塑物，对于控制基因表达至关重要。它们的活性是正常发育所必需的，在几乎25%的癌症中被破坏。SWI/SNF复合物存在于哺乳动物中的三个不同的亚类，它们从它们的进化前体中显著地多样化。然而，这种多样性的原因仍然是谜;这构成了我们对这个重要的基因调控系统的理解的主要概念差距。我最近发现了一个特殊的功能作用的SWI/SNF亚类之一，在儿科恶性肿瘤，滑膜肉瘤。现在，我提出每个SWI/SNF亚类都有独特的/依赖于上下文的功能，这可能与疾病生物学相关。基于我的发现，在BAFDefiner中，我正在追求一个雄心勃勃的，假设驱动的计划，整合生物化学，基因组和单细胞分析，以发现不同SWI/SNF亚类的特定功能。具体来说，我的三个目标是：（i）以生物化学的方式确定不同SWI/SNF亚类的组成（ii）发现不同SWI/SNF亚类的独特功能（iii）确定SWI/SNF成员在单细胞分辨率下的调节作用为此，我正在开发新的实验工具，使用化学生物学和单细胞基因组学的方法来功能性地剖析细胞中不同的SWI/SNF亚类。实施这些方法将使我获得远远超出当前实验技术的见解。将我们对SWI/SNF复杂生物学的理解推进到未来几十年;所有这些都在本研究计划的范围内。这将缩小目前限制我们对SWI/SNF复合物多样性的理解的概念差距，也许最重要的是，这是设计治疗策略以干预SWI/SNF功能被破坏的癌症（和其他疾病）的重要一步。

The SWI/SNF family of complexes are chromatin remodellers, essential for controlling gene expression. Their activities are necessary for normal development and are disrupted in almost 25% of all cancers. Three distinct subclasses of SWI/SNF complex exist in mammals, which have diversified significantly from their evolutionary precursors. However, the reasons for this diversification remain enigmatic; which constitutes the major conceptual gap in our understanding of this essential gene regulatory system. I recently discovered a specific functional role for one of the SWI/SNF subclasses in the paediatric malignancy, synovial sarcoma. Now, I propose that each SWI/SNF subclass has unique/context-dependent functions, which likely have relevance in disease biology. Building on my discovery, within BAFDefiner I am pursuing an ambitious, hypothesis driven program, integrating biochemical, genomic and single-cell analyses to discover the specific functions of the distinct SWI/SNF subclasses.Specifically, my three aims are:(i) To biochemically define the compositions of distinct SWI/SNF subclasses(ii) To discover the unique functions of distinct SWI/SNF subclasses(iii) To define the regulatory roles of SWI/SNF members at single-cell resolutionTo do this, I am developing novel experimental tools using approaches in chemcial biology and single-cell genomics to functionally dissect distinct SWI/SNF subclasses in cells. Implementing these approaches will allow me to derive insights that are well beyond current experimental techniques. Moving our understanding of SWI/SNF complex biology decades into the future; all within the term of this research program. This will close the conceptual gap that currently limits our understanding of SWI/SNF complex diversity, and perhaps most importantly, is an essential step towards devising therapeutic strategies to intervene in cancers (and other diseases) where SWI/SNF function(s) are disrupted.