BAF complexes in T cell development

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DESCRIPTION (provided by applicant): Mammalian Swi/Snf-related BAF complexes are ubiquitously expressed, prototypical "ATP-dependent chromatin remodeling complexes" that can use energy to manipulate nucleosome structure in response to external signals. BAF mutations are linked to multiple human tumors, but the physiological functions of BAF complexes are poorly understood. Our long-term goals are to use T cell development as model systems to identify physiological target genes of BAF complexes, to dissect the mechanisms by which BAF complexes regulate these genes, and to understand how BAF complexes respond to signaling pathways. We have found that deleting the ATPase subunit Brg produces multiple defects in T cell development, some of which are recapitulated by mutations in BAF57, an HMG-box protein. Paradoxically, BAF57 as well as many other subunits of BAF complexes are dispensable for the classical Brg-catalyzed, ATP-dependent remodeling in vitro. We hypothesize that the "dispensable" subunits can regulate gene expression by novel mechanisms independent of Brg-mediated chromatin remodeling, and by stimulating remodeling of the target genes in their natural chromatin contexts. Using a combination of genetic and biochemical methods, we will attempt to identify the putative ATP-independent BAF functions in gene regulation during T cell development, to probe the molecular basis of such functions, and finally to determine whether BAF57 can help Brg to remodel endogenous target genes. These studies will enhance our understanding of T cell development, and are of general interest: they take on a major challenge in the chromatin field, which is to address the in vivo functions of chromatin remodelers especially those mediated by their dispensable subunits. In addition, our studies are of practical value, given the roles of BAF complexes in tumorigenesis.