Chromatin Assembly Structure and Function

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DESCRIPTION (provided by applicant): The packaging of the eukaryotic genome together with histone proteins into chromatin has profound implications for all processes that occur on the DMA template, including replication, transcription and repair. Chromatin assembly and disassembly are essential for duplication of the genome, yet are poorly understood. Recent studies (including our own) have discovered that chromatin assembly and disassembly, independent of genome duplication, are novel and important means of transcriptional regulation. The long-term goal of this project is to generate a unified understanding of how chromatin disassembly and reassembly regulate transcription. We have uncovered a novel precursor of chromatin disassembly where a transcriptional activator is bound near the dyad axis of symmetry of a nucleosome in vivo, prior to nucleosome disassembly. Our first goal therefore is to identify the chromatin changes that enable activators to destabilize a nucleosome enough to drive chromatin disassembly. Our second goal is to discover the fundamental molecular mechanisms whereby promoter chromatin disassembly and reassembly are essential for transcriptional activation and repression, respectively. The proposed research will also discern whether the ultimate target of histone modifications is to regulate chromatin disassembly and reassembly, and may identify the epigenetic mark that is sufficient to maintain a naked DNA state through replication. Our third goal is to characterize the novel role that we have discovered for the proteasome in chromatin disassembly. By continuing to use molecular genetic analyses focusing on the well-characterized budding yeast PH05 promoter coupled with biochemistry and structural approaches, we are uniquely positioned to fill critical gaps in the current understanding of the fundamental regulation and inheritance of transcription programs. The highly conserved nature of transcriptional regulation mechanisms across eukaryotic species indicates that our findings will be directly applicable to the analysis of human diseases, including many forms of cancer that involve defects in chromatin-utilizing processes. Relevance to the public health. Many diseases are the result of incorrect gene expression. The mechanistic understanding of chromatin assembly and disassembly that will come from this work will further our ability to modify the epigenetic codes involved in human diseases for the purpose of therapeutic intervention.