Differential Roles of SWI/SNF Complexes in Metal Regulation

SWI/SNF complexes play a major role in chromatin remodeling in mammalian cells. Mammalian DNA is compacted into chromatin by nucleosomes and other factors. The level of compaction is regulated largely by SWI/SNF complexes. These complexes remodel nucleosomes by displacing or evicting them, or by exchanging histones. By controlling which areas of the chromatin are available for transcription, SWI/SNF complexes have a large impact on gene expression. There are three main classes of SWI/SNF complexes: Brg/Brm-associated factor (BAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF). We hypothesized that these distinct classes of SWI/SNF complexes may have different roles, and respond to environmental and cellular signals in a specific manner. Preliminary data from our lab showed that the PBAF, and potentially the BAF complexes, may play a role in stress, homeostasis, and metal regulation in proliferating and differentiating myoblasts. We used cultured C2C12 myoblasts partially depleted of a representative subunit of each SWI/SNF complex, as these cells have an intrinsic high demand for transition metals for proper growth, differentiation, and function. Knock-down myoblasts were treated with sublethal concentrations of different metals, and we analyzed the correlation of each SWI/SNF complex with the expression of the metal protective transcription factor (Mtf1) and metal responsive metallothionein-1 (Mt1) genes. Our work provides the first mechanistic evidence of the contribution of specific chromatin remodelers to the expression of the main metal protective transcription factor and effector genes necessary for surviving metal toxicity. © FASEB.