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，对发育和成年生物体至关重要。我的研究方向是了解控制细胞可塑性的调控机制。一种称为上皮-间质转化（EMT）的细胞过程与细胞可塑性有关。EMT是发展的基础。经历EMT的细胞从具有细胞间接触、顶基极性、存在E-cadherin等上皮标记物的上皮性细胞转变为具有形状和标记物表达的成纤维细胞，肌动蛋白也从皮质样细胞转变为应激纤维样细胞。接受EMT的细胞可以恢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能力的机制。众所周知，TGF等信号蛋白可诱导EMT，并与发育和体内平衡有关。乳腺的发育主要发生在出生后。EMT已被认为有助于分支形态的形成。我们使用乳腺上皮细胞来揭示控制EMT的调节机制。我们发现小泛素样修饰物（SUMO）系统通过靶向特定底物进行SUMO化来调节emt相关的细胞可塑性。我们的发现也提出了sumo依赖通路调节emt相关细胞表型的分子机制的关键问题。染色质致密性和调控（表观遗传学）在控制最终可能表现为特定表型的基因表达方面发挥关键作用，例如在EMT中。然而，如何调节这些表观遗传过程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研究特定的sumo途径的作用，该途径通过促进转录调节因子SnoN的sumo化，从而抑制乳腺上皮细胞以三维方式生长的EMT。基于初步数据，我们建议研究SnoN与特定染色质重塑因子之间的联系，以调节EMT的细胞塑性过程。这项研究将为EMT和细胞可塑性是如何被调节的提供新的见解。

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 TGF 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.