Every cell in the human body relies on a set of molecular machines called SWI/SNF complexes to keep its genes switched on or off in the right pattern—and in nearly one in four cancers, these machines are broken. Despite their importance, scientists do not understand why mammals have three distinct versions of this complex, each of which appears to have evolved separately. This gap in fundamental knowledge blocks progress in treating cancers where SWI/SNF function goes wrong. The researcher recently discovered that one specific subclass drives a childhood cancer called synovial sarcoma, and now aims to map the unique jobs of all three subclasses. Using new chemical and single-cell tools, this project will define exactly what each complex does and how it controls gene activity in individual cells. The work is fundamental science—it will not produce a drug tomorrow. But understanding these core gene-regulating machines is an essential step toward designing therapies that fix or bypass the broken complexes in cancers and other diseases where they are disrupted.
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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 resolution To 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.
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