Book Description

Mammalian SWI/SNF (also called BAF) ATP-dependent chromatin remodeling complexes are essential for formation of the pluripotent cells of the early embryo, and are also crucial for the self-renewal and pluripotency of mouse embryonic stem cells (ESCs). To understand the molecular mechanism of BAF complexes in regulating the chromatin of pluripotent stem cells, we performed both proteomic and genomic studies of endogenous complexes in ESCs. Proteomic studies reveal that ESCs express distinctive BAF complexes (esBAF), and this specialized subunit composition is required for ESC maintenance and pluripotency. High-resolution genome-wide mapping of the core ATPase subunit, Brg, using ChIP-Seq technology indicates that esBAF is a core component of the pluripotent transcriptional network. This is consistent with findings that esBAF interacts both physically and genetically with key regulators of pluripotency such as Stat3, Oct4 and Sox2. In addition, esBAF is critical for Stat3-mediated gene activation and repression in mESCs in response to Leukemia Inhibitory Factor (LIF), the cytokine that maintains mESCs in a self-renewing state. Brg maintains open accessibility of Stat3 target sites to allow continuous binding of Stat3 in response to LIF signaling, and prevents the expansion of Polycomb activity and the inappropriate deposition of the silencing mark H3K27me3 at both Stat3 targets and other sites. We propose that one integral mechanism of esBAF action in maintaining pluripotency is to maintain Stat3 responsiveness in ESCs by regulating the accessibility of its target sites. The role of BAF complexes in self-renewal and differentiation extend to adult multipotent stem cells. Using mouse adult hematopoietic development as a model, we show that Brg is required for the transition of quiescent long-term hematopoietic stem cells (LT-HSCs) to their downstream progenitors, and for the multilineage differentiation of transit amplifying hematopoietic progenitors. Hence, we propose that chromatin remodeling is generally required for the function and maintenance of stem cells by the regulation of their specialized chromatin landscape.