Discovering the function of distinct SWI/SNF complexes

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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.