We are interested in understanding how accessible chromatin is established at regulatory regions of cell-type specific genes during differentiation to allow their expression in mature cells. We are using the mouse hematopoietic system and in particular bone marrow derived macrophages as a model for differentiation. Macrophages differentiated in vitro from hematopoietic progenitors can be stimulated by various bacterial and viral agents to express innate immune response genes such as pro-inflammatory cytokines. Studies by the lab have revealed that transcriptional enhancers of pro-inflammatory cytokines are occupied by intermediate levels of nucleosomes in resting macrophages, and are cleared of nucleosomes when cells are stimulated with bacterial lipopolysaccharides (LPS). Current efforts aim at understanding how lineage-specific pioneer transcription factors (TFs) and nucleosome remodelers cooperate to keep chromatin at cytokine enhancers accessible during macrophage differentiation.
Understanding how pro-inflammatory genes are regulated is of great interest to the medical community, since chronic inflammation plays a role in many diseases, including atherosclerosis and heart disease. Dr. Floer currently holds a grant from the American Heart Association to investigate the roles of the pioneer TF PU.1 and the SWI/SNF nucleosome remodelers BAF and PBAF in regulating cytokine expression. Studies in this system are expected to lead to novel insights into chromatin regulation that will apply to other systems. For example, mutations in specific subunits of these nucleosome remodelers are found in 20% of all human cancers, including chronic lymphoid leukemias, yet the role of individual subunits in regulating remodeler function is unclear. Other leukemias, such as acute myeloid leukemias, are associated with misregulation of PU.1, indicating that this TF plays an important role in cellular differentiation. Our studies of the roles of pioneer TFs and nucleosome remodelers during macrophage differentiation will likely reveal general principles of chromatin regulation, which has the potential to lead to novel therapeutic approaches to prevent and treat cancer.