Chromatin structure and gene regulation

In order to package the large quantities of DNA that make up the genomes of eukaryotes into the nuclei of cells, it is associated with proteins to form a condensed nucleoprotein complex termed chromatin. Although the formation of chromatin helps to package DNA within the nucleus, it also presents an impediment to any process that requires access to the genetic information. It is now clear that the remodeling of chromatin structure represents a key stage in gene function and that the remodeling step can itself be the target of regulatory pathways. There are now many examples to illustrate the importance of chromatin unfolding in biological processes as diverse as sexual differentiation, development, thalassemia, cancer and gene therapy.

Over the last decade intense general interest in the subject has resulted in major new insights as to how chromatin is unfolded during gene regulation. Multiprotein complexes have been identified that function to modify the structure of chromatin during gene regulation. These include ATP-dependent chromatin remodeling activities that use the energy derived from ATP hydrolysis to alter chromatin accessibility and enzymes that modify chromatin structure by covalent post-translational modification. We are interested in determining the mechanisms by which these molecular remodeling machines co-operate to alter chromatin structure. Although to date we have relied heavily upon the use of biochemical systems, in future, we will adopt a multi-disciplinary approach including the application of both structural biology and in vivo assays to study the fundamental processes by which access to the genome is regulated.

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