Chromatin plays critical roles in processes governed in different time scales in response to environmental changes and requires rapid plasticity, while long term stability through multiple cell generations requires epigenetically heritable chromatin. It is of great interest, therefore, to understand the nature of dynamic chromatin states in living cells. We have developed tools that enable rapid measurement of chromatin structure at high resolution over a significant fraction of the yeast genome, and our lab has recently extended the use of these tools to measure histone H3 replacement dynamics across the entire yeast genome in G1-arrested yeast. Our preliminary data lead us to ask the following questions. What are the mechanisms for histone replacement in the absence of genomic replication? How do replacement rates differ for H3/H4 and H2A/H2B? Can we mechanistically separate those two processes? Is acetylation of H3K56 required for histone replacement, and what is its role during G1 arrest? How does histone replacement change during the cell cycle, and how do processes such as heterochromatin silencing and chromosome cohesion influence histone replacement? Does nucleosome replacement act to insulate chromatin domains from one another? Most of these questions can only be adequately addressed by genomic analysis, since in many cases single locus studies can be misleading. We have pioneered several techniques for genomic analysis of chromatin structure, and are ideally positioned to carry out the proposed studies. Taken together, the proposed studies will provide an immensely valuable window into the dynamic nature of chromatin. We will identify mechanisms of histone replacement, and will determine the role of cell cycle in regulation of the stability of chromatin compaction states. These experiments will greatly further our basic knowledge of chromatin structure, will expand our understanding of transcriptional control, and will constrain any models for the stable inheritance of chromatin states. Epigenetic inheritance, the inheritance of information beyond DNA sequence, underlies the differences between different cell types in the human body. In the past decade it has become increasingly clear that epigenetic defects, in addition to genetic mutations, play a major role in cancer. In this proposal we aim to investigate the mechanisms that enable cells to inherit epigenetic information, with the hope that we may eventually use this information to design more directed therapies against cancer. ? ? ?
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