Regulation of Cellular Plasticity

细胞可塑性，被定义为细胞以可逆的方式改变其表型的能力，对于发育中的和成年的生物体来说是至关重要的。我的研究项目感兴趣的是了解控制细胞可塑性的调控机制。一种称为上皮-间充质转化(EMT)的细胞过程与细胞的可塑性有关。EMT是企业发展的基础。经EMT后的细胞从细胞-细胞接触、尖-基底极性和存在E-钙粘蛋白等上皮性标志物转变为成纤维细胞，其形态和标志物的表达以及肌动蛋白从皮质改变为应力纤维样。接受EMT的细胞可以回复到获得全部或部分上皮表型。该领域的一个主要问题是调节细胞接受EMT的能力的机制。众所周知，像转化生长因子一样的信号蛋白可以诱导与发育和动态平衡相关的EMT。乳腺的发育主要发生在出生后。EMT被认为对分枝形态发生有贡献。我们使用乳腺上皮细胞来揭示控制EMT的调控机制。我们已经发现，小泛素样修饰物(SUMO)系统通过靶向特定底物的SUMO作用来调节EMT相关的细胞可塑性。我们的发现还提出了一个关键问题，即相扑依赖通路调节EMT相关细胞表型的分子机制。染色质的紧凑性和调节(表观遗传学)在控制最终可能表现为特定表型的基因的表达方面起着关键作用，例如在EMT中。然而，这些表观遗传过程如何被调节来控制细胞表型仍然知之甚少。本申请中描述的拟议研究将调查特定相扑通路的作用，该通路通过促进转录调节因子SnoN的相扑作用，进而抑制以三维方式生长的乳腺上皮细胞中的EMT。基于初步数据，我们建议研究SnoN与特定染色质重构体之间的联系，以调控EMT的细胞可塑性过程。这项研究将为EMT和细胞可塑性的调控提供新的见解。

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.