Determinants of higher order genome architecture

我的研究项目将调查DNA的三维结构——基因组是如何“包装”的——如何决定细胞的身份。这个研究问题将加深我们对构成我们身体不同组织和器官的细胞如何具有不同功能的理解（它们可以是皮肤细胞、肌肉细胞或神经元等），尽管它们都共享相同的基因组。我们的工作将建立在我们最近的发现上，即一类被称为组蛋白变体的蛋白质在以不同方式包装具有不同功能的细胞中的DNA方面发挥作用。在NSERC的资助下，我的研究小组将确定导致人类大脑中干细胞及其后代（神经元、星形胶质细胞和少突胶质细胞）之间DNA包装差异的组蛋白变体。我们的研究将破译连接特定DNA结构和细胞功能的密码。这项研究对自然科学有着深远的影响。首先，我们将发展DNA包装编程特定细胞功能的新概念。因此，我们将产生新的知识和工具，这些知识和工具将很容易适用于研究其他发育系统或疾病模型的科学家，因此我们的工作也有可能为其他领域的发现播下种子。其次，近年来，再生医学的重点是将给定的细胞转化为另一种细胞类型，例如，将受神经系统疾病影响的患者的皮肤细胞分化为可以重新移植到同一患者体内的健康神经元。由于特定细胞的DNA结构所形成的分化障碍阻碍了这种努力，从而阻止了转化为其他类型的细胞。通过显著提高我们对基因组结构和细胞功能之间关系的理解，我们的工作将为帮助再生医学努力获得可用于临床目的的适当分化细胞开辟新的机会。第三，改变染色质结构变得越来越容易，因为针对染色质重塑酶的化合物越来越多，其中一些已经被批准用于人类受试者。我们的研究所产生的知识将为结合特定染色质重塑化合物的靶向方法提供信息，以设计3D基因组结构中所需的变化并获得特定的细胞类型。第四，我们的研究将产生区分细胞类型的DNA结构“指纹”。鉴于我们对DNA结构和细胞功能之间紧密关联的新兴理解，我们的研究计划将提供人类细胞功能特性的前所未有的观点。

My research program will investigate how the three-dimensional architecture of the DNA - how the genome is "packaged" - determines the identity of a cell. This research question will deepen our understanding of how cells that make up different tissues and organs in our bodies have different functions (they can be skin cells, or muscle cells, or neurons, etc) although they all share the same genome. Our work will build on our recent findings that a class of proteins called histone variants have a role in packaging the DNA in different ways in cells that have different functions. With NSERC funding, my research group will identify the histone variants that are responsible for differences in DNA packaging between stem cells and their progeny (neurons, astrocytes and oligodendrocytes) in the human brain. Our studies will decipher the code that links a specific DNA architecture with cellular function. The implications of this research for the natural sciences are far reaching. First, we will develop the new concept of DNA packaging programming specific cell functions. We will therefore generate new knowledge and tools that will be readily adapted to scientists working with other developmental systems or with disease models, thereby our work has the potential to seed discoveries in other fields as well. Second, there has been significant emphasis in recent years on regenerative medicine initiatives to convert a given cell into another cell type, for instance differentiating skin cells from a patient affected by a neurological disease into healthy neurons that can be retransplanted into the same patient. Such efforts have been hampered by differentiation barriers erected by the DNA structure of a given cell, which prevents conversion into other cell types. By significantly improving our understanding of the relationship between genome architecture and cell function, our work will open new opportunities to aid regenerative medicine efforts to obtain properly differentiated cells that can be used for clinical purposes. Third, altering chromatin architecture is becoming increasingly easy because of the growing arsenal of compounds that target chromatin remodelling enzymes, some of which have already been approved for use in human subjects. The knowledge generated by our studies will inform targeted approaches that combine specific chromatin remodelling compounds to engineer the desired changes in 3D genome architecture and obtain specific cell types. Fourth, our studies will generate DNA architecture "fingerprints" that will distinguish between cell types. Given our emerging understanding of the tight correlation between DNA architecture and cell function, our research program will offer an unprecedented view of the functional properties of human cells.