Regulation of Cellular Plasticity

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Cellular plasticity, defined as the ability of cells change their phenotype in a reversible manner, is critical for the developing and adult organism. My research program is interested in understanding the regulatory mechanism that control cellular plasticity. A cellular process called epithelial-mesenchymal transition (EMT) is associated with cellular plasticity. EMT is a fundamental in development. Cells undergoing EMT change from being epithelial nature, where there are cell-cell contact, apical-basal polarity, and presence of epithelial marker like E-cadherin, to becoming fibroblastic in terms of shape and expression of markers and the change of actin from being cortical to stress fiber like. Cells undergoing EMT can revert back to acquire all or part of the epithelial phenotypes. A major question in the field is the mechanisms that regulate the ability of cells to undergo EMT. It is well established that signaling proteins like TGFß can induce EMT with relevance for development and homeostasis. Development of the mammary glands occurs largely postnatally. EMT has been suggested to contribute the branching morphogenesis. We use mammary epithelial cells to uncover the regulatory mechanisms controlling EMT. We have discovered that the small ubiquitin like modifier (SUMO) system regulate EMT-associated cellular plasticity through targeting specific substrates for sumoylation. Our findings have also raised the key question of the molecular mechanisms by which the SUMO-dependent pathways regulate EMT-associated cellular phenotypes. Chromatin compactness and regulation (epigenetics) play key roles in controlling expression of genes that ultimately may manifest as specific phenotype, eg as in EMT. However, how these epigenetic processes are modulated to control cell phenotype remain poorly understood. The proposed research described in this application will investigate the role of specific sumo pathways that by promoting sumoylation of the transcriptional regulator SnoN which in turn suppress EMT in mammary epithelial cells grown in a three-dimensional manner. Based on preliminary data, we propose to study the link between SnoN and specific chromatin remodelers to regulate the cellular plastic process of EMT. This research will add new insights into how EMT and cellular plasticity are regulated.