Determinants of higher order genome architecture

高阶基因组结构的决定因素

• 批准号: RGPIN-2017-04120
• 负责人: Gallo, Marco
• 金额: $ 2.26万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=683815
• 关键词: Determinants; higher; order; genome; architecture

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.

我的研究计划将研究 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体内不同组织和器官的细胞（它们可以是皮肤细胞、肌肉细胞或神经元等）如何具有不同功能的理解，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之上，即一类称为组蛋白变体的蛋白质在具有不同功能的细胞中以不同方式包装 DNA 方面发挥着作用。在 NSERC 的资助下，我的研究小组将鉴定导致人脑干细胞及其后代（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。我们的研究将破译将特定 DNA 结构与细胞功能联系起来的代码。这项研究对自然科学的影响是深远的。首先，我们将开发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应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在其他领域播种发现。其次，近年来人们非常重视将特定细胞转化为另一种细胞类型的再生医学举措，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。这种努力受到了特定细胞 DNA 结构所建立的分化障碍的阻碍，这种分化障碍阻止了向其他细胞类型的转化。通过显着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的细胞开辟新的机会。第三，由于针对染色质重塑酶的化合物不断增加，改变染色质结构变得越来越容易，其中一些已经被批准用于人类受试者。我们的研究产生的知识将为结合特定染色质重塑化合物的有针对性的方法提供信息，以设计 3D 基因组结构所需的变化并获得特定的细胞类型。第四，我们的研究将生成能够区分细胞类型的 DNA 结构“指纹”。鉴于我们对 DNA 结构和细胞功能之间紧密相关性的认识不断加深，我们的研究项目将为人类细胞的功能特性提供前所未有的视角。