BAF complex in T cell development and function

The BAF complex is a ten subunit complex which contains an ATPase subunit, Brg or Brm, that uses energy derived from ATP hydrolysis to disrupt histone:DNA contacts to catalyze transcriptional events such as promoting gene expression or repression. The canonical view of the BAF complex as an ATPase-dependent chromatin remodeler is misleading because in vitro studies have shown that only four subunits of the BAF complex are necessary to remodel chromatin. This leads to an important question---are there ATPase-independent functions of the BAF complex? Using a novel genetic strategy we have been able to study the ATPase-dependent and---independent functions of the BAF complex at different stages of T cell development. Previous work characterizing the role of BAF complex in T cell development has shown it plays a crucial role in supporting the DN to DP transition and it also plays an important role in CD4 gene regulation. Using mice harboring a Cre transgene expressed at the DN stage, we show that the DN to DP transition is largely ATPase-dependent, while ATPase-dependent and independent functions play a role in CD4 gene regulation. Interestingly, our studies using mice bearing a Cre transgene expressed at the DP stage reveal that although BAF complex is not required for CD4 expression in DP or SP cells, it plays important roles in thymic selection processes, particularly in the Raf-MEK-Erk signaling axis, that promote the DP to SP transition as well as thymic Treg development. In the periphery, we find that ATPase dependent and independent functions have important effects on Th1/2 cytokine expression as well as Th1/2 commitment. Additionally, BAF complex promotes self-tolerance by promoting Treg survival and the expression of anti-inflammatory genes in Tregs. Our work reveals important ATPase-dependent and---independent functions of the BAF complex in T cell development and function.