Packaging the eukaryotic genome into chromatin allows all genomic processes, and consequently growth, development and differentiation, to be highly regulated. This is because our cells use a plethora of mechanisms to change the chromatin structure into a more compact or less compact state, in order to regulate localized access to the genome by the machinery that mediates gene expression, DNA repair, and replication. In the Tyler lab, we study the most profound way that the chromatin structure is changed in the cell, which is removal of the histone proteins from the DNA, termed chromatin disassembly and the opposite process of chromatin assembly. These processes are mediated by histone chaperones together with ATP-dependent chromatin remodelers. Over the years, my group and others have shown that chromatin disassembly and reassembly occurs during replication, gene expression and DNA double-strand break repair. By inactivating the machinery involved in chromatin disassembly and reassembly, we have shown that these chromatin dynamics play an important role in regulating these fundamental genomic processes. However, we still do not know how chromatin disassembly is triggered and how chromatin reassembly occurs in a coordinated fashion at the right time and right place. We will answer these questions by taking advantage of inducible DNA double- strand break systems. It is also important to repress the transcription of genes around a DNA double-strand break in order to achieve DNA repair and to restart transcription after DNA repair is complete. The mechanisms for this are unknown, but we will test the hypothesis that chromatin disassembly and reassembly play important roles in the regulation of transcription inhibition and restart around sites of DNA double-strand damage. Given that the key histone chaperones that mediate these processes, Asf1 and CAF-1, are overexpressed in many types of cancer, this work will not only fill large knowledge gaps but will also have relevance for understanding carcinogenesis.
Gaining a thorough mechanistic understanding of how chromatin assembly and disassembly regulates nuclear processes is important to be able to fill critical gaps in our current knowledge of how these nuclear processes are controlled. In the long term, this knowledge will help us better understand the mechanistic basis of human diseases where these processes go awry, in addition to helping identify molecular targets for the design of therapeutics, in order to inactivate these nuclear processes.
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