Structural and functional studies of histone acetyltransferase complexes

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Much like a recipe book, the human genome contains detailed instructions for building a multi-cellular human being. This recipe book, written in the form of genomic DNA, is organized into ~20,000 individual “chapters” called genes, encoding proteins in the human body. Although every one of the trillions of living cells in the human body contains an identical copy of this genomic DNA, each cell only uses a subset of these genes to make proteins at any given time, and this is what differentiates, for example, a liver cell from a muscle cell. A formidable challenge in life science research is to determine how, at the molecular level, a cell precisely selects which genes to express at a given time and context. Genomic DNA in our cells is organized into a dense structure known as chromatin, which involves wrapping of DNA around a scaffold made by proteins called histones, in the nucleus of a cell. One way that a cell regulates (turns on or off) gene expression is by “labeling” these histone proteins with different chemical groups to mark which genes will be active or remain inactive in that cell type. These labels or “chromatin modifications” are “written” and “erased” by ensemble group of specialized “protein nanomachines” known as chromatin-modifying complexes. The long-term objective of my research program is to understand the molecular mechanisms of how chromatin-modifying complexes selectively modify histones and regulate gene expression. My first NSERC Discovery Grant has enabled my trainees and me to establish an integrated experimental platform for characterizing the biochemical properties of chromatin-modifying complexes. This platform allowed us to complete three pilot studies that generated novel understanding of the molecular structures of three representative members from a specialized group of chromatin-modifying complexes known as histone acetyltransferase (HAT) complexes. Building on this foundation, we are proposing to apply a cutting edge molecular imaging approach known as cryo-electron microscopy (cryo-EM) to visualize, at atomic level detail, how the different components are arranged within these complexes and how they work in concert with one another to add chemical labels to modify histones. Knowledge gained from this research will help fill a key knowledge gap in our understanding of how gene expression pattern is established and altered during cell differentiation and the development of a multicellular organism. The HQP involved in this research program will gain unique opportunities to develop advanced technical skills such as cryo-EM, project management, communications, and scientific writing skills that would allow them to be highly competitive in the research-oriented job market and contribute to the growth of Canada's knowledge-driven economy.