Structural and functional studies of histone-modifying complexes

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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.