Structural and functional studies of histone-modifying complexes

就像一本百科全书一样，人类基因组包含了构建人类的所有指令。这个百科全书以DNA的形式组织成20，000个单独的“章节”或称为基因的功能单位。我们体内数万亿个活细胞中的每一个都含有这种DNA的相同副本。然而，每个细胞只使用或表达一组特定的基因，这就是肝细胞与肌肉细胞的区别。目前基因组科学研究的一个主要挑战是确定细胞如何在基因组中发现的许多基因中选择哪些基因来表达。在细胞中，我们的DNA是通过包裹在由称为组蛋白的蛋白质组成的支架上来组织的。为了使基因表达发生，DNA必须从这种称为染色质的DNA-蛋白质复合物中解旋。染色质结构和组织的变化涉及组蛋白的修饰，这些修饰由几组大的多亚基蛋白质复合物进行。我的研究计划的长期目标是确定不同组蛋白修饰复合物如何识别哪些组蛋白进行修饰，以及这些复合物如何相互协调以改变染色质结构。利用我们在称为单粒子电子显微镜的尖端成像方法方面的独特专业知识，我和我的研究小组将在分子水平上研究组蛋白修饰复合物的结构特性。我们还将使用其他生物化学和分子生物学方法来研究这些复合物如何结合和修饰组蛋白。从这项研究中获得的知识将对提高我们对基因表达模式在细胞分化和多细胞生物体发育过程中如何建立、改变和维持的理解产生重大影响。

Much like an encyclopedia, the human genome contains all the instructions for building a human being. This encyclopedia, in the form of DNA, is organized into 20,000 individual "chapters" or functional units called genes. Each and every one of the trillions of living cells in our body contains an identical copy of this DNA. However, each cell uses or expresses only a specific set of the genes, and this is what differentiates, for example, a liver cell from a muscle cell. A major challenge in genome science research right now is to determine how a cell selects which genes, amongst the many found in the genome, to express. In the cell, our DNA is organized by wrapping around a scaffold composed of proteins called histones. To allow gene expression to occur, the DNA must be unwound from this DNA-protein complex known as chromatin. Changes to chromatin structure and organization involve modifications to histones, and these modifications are carried out by several groups of large, multi-subunit protein complexes. The long-term objective of my research program is to determine how the different groups of histone modifying complexes identify which histones to modify and how these complexes coordinate with each other to change chromatin structure. Using our unique expertise in a cutting edge imaging method called single-particle electron microscopy, my research group and I will examine the structural properties of histone modifying complexes at the molecular level. We will also use other biochemical and molecular biology methods to examine how these complexes bind and modify histones. Knowledge gained from this research will have a major impact in improving our understanding of how gene expression pattern is established, altered, and maintained during cell differentiation and the development of a multicellular organism.