Discovering the function of distinct SWI/SNF complexes

发现不同 SWI/SNF 复合物的功能

• 批准号: EP/X039633/1
• 负责人: Gerard Brien
• 金额: $ 164.66万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX039633%2F1
• 关键词: Discovering; function; distinct; SWI; SNF

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.

SWI/SNF复合体家族是染色质重构体，对控制基因表达是必不可少的。它们的活动是正常发育所必需的，在几乎25%的癌症中都受到干扰。哺乳动物中存在三个不同的SWI/SNF复合体亚类，它们与它们的进化前体有很大的差异。然而，这种多样化的原因仍然是个谜；这构成了我们对这一基本基因调控系统理解的主要概念鸿沟。我最近发现SWI/SNF亚类中的一个亚类在儿童恶性肿瘤滑膜肉瘤中具有特定的功能作用。现在，我提出每个SWI/SNF亚类都有独特的/上下文相关的功能，这可能与疾病生物学有关。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，整合生化、基因组和单细胞分析，以发现不同SWI/SNF亚类的特定功能。具体地说，我的三个目标是：(I)以生物化学方式定义不同SWI/SNF亚类的组成(Ii)发现不同SWI/SNF亚类的独特功能(Iii)定义SWI/SNF成员在单细胞分辨率中的调节角色。实施这些方法将使我能够获得远远超出当前实验技术的见解。将我们对SWI/SNF复杂生物学的理解移到几十年后的未来；所有这些都在本研究计划的期限内。这将弥合目前限制我们理解SWI/SNF复合体多样性的概念鸿沟，或许最重要的是，这是朝着设计治疗策略的关键一步，以干预SWI/SNF功能中断的癌症(和其他疾病)(S)。