Mammalian SWI/SNF-related complexes are required for tissue specific gene expression. The components of these complexes are evolutionarily conserved, and were first identified in yeast, where they are required for the changes in gene expression that mediate the mating type switch (SWI) and the ability to switch to sucrose utilization in the absence of glucose (Sucrose-Non-Fermentors). The complexes contain a DNA-dependent ATPase activity that powers a nucleosome remodeling function, which in turn allows transcription factor access to promoter sites. The yeast complexes have been the target of extensive genetic analysis, and considerable work has been done to address the mechanisms of nucleosome remodeling by yeast and mammalian complexes, but surprisingly little is known about the biological role of the complex and its individual components in the differentiation of mammalian cells. What is known is that abrogation of the ATPase activity of the complex blocks normal differentiation function in a range of tissue types. The ATPase is the molecular motor of the complex and is, of course essential to its function, but the complexes contain seven or more other components that are believed to modulate the activity of the complex in response to specific signals, particularly in response to hormones. Very limited information is available on the biological role of these modulatory, non-catalytic, subunits. Elucidation of their roles would give much-needed insight into how the complexes achieve specificity of function in precisely regulated metabolic processes. This project therefore proposes the development of differentiation models in which specific complex components will be depleted individually within a single biological system. The resulting phenotypes will indicate the biological roles of the individual subunits. The differentiation models will be developed in a pre-osteoblast line because these cells are responsive to multiple extracellular signals and have a highly regulated and sequential differentiation program that is well-characterized and includes cell cycle regulation. The proposed systems will provide important clinical data, relevant to broad public health problems, such as osteoporosis and inflammatory diseases, as well as to cancer.
| Nguyen, Kevin Hong; Xu, Fuhua; Flowers, Stephen et al. (2015) SWI/SNF-Mediated Lineage Determination in Mesenchymal Stem Cells Confers Resistance to Osteoporosis. Stem Cells 33:3028-38 |
| Flowers, Stephen; Patel, Parth J; Gleicher, Stephanie et al. (2014) p107-Dependent recruitment of SWI/SNF to the alkaline phosphatase promoter during osteoblast differentiation. Bone 69:47-54 |
| Flowers, Stephen; Xu, Fuhua; Moran, Elizabeth (2013) Cooperative activation of tissue-specific genes by pRB and E2F1. Cancer Res 73:2150-8 |
| Xu, Fuhua; Flowers, Stephen; Moran, Elizabeth (2012) Essential role of ARID2 protein-containing SWI/SNF complex in tissue-specific gene expression. J Biol Chem 287:5033-41 |
| Siqueira, Michelle F; Flowers, Stephen; Bhattacharya, Rupa et al. (2011) FOXO1 modulates osteoblast differentiation. Bone 48:1043-51 |
| Flowers, Stephen; Beck Jr, George R; Moran, Elizabeth (2011) Tissue-specific gene targeting by the multiprotein mammalian DREAM complex. J Biol Chem 286:27867-71 |
| Flowers, Stephen; Beck Jr, George R; Moran, Elizabeth (2010) Transcriptional activation by pRB and its coordination with SWI/SNF recruitment. Cancer Res 70:8282-7 |
| Flowers, Stephen; Nagl Jr, Norman G; Beck Jr, George R et al. (2009) Antagonistic roles for BRM and BRG1 SWI/SNF complexes in differentiation. J Biol Chem 284:10067-75 |
| Nagl Jr, Norman G; Wang, Xiaomei; Patsialou, Antonia et al. (2007) Distinct mammalian SWI/SNF chromatin remodeling complexes with opposing roles in cell-cycle control. EMBO J 26:752-63 |
