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Current work in the laboratory of James B. Jaynes is focused on understanding two major aspects of nuclear genome regulation in eukaryotic organisms that affect genome organization in 3 dimensions. We and others have shown that these regulatory systems have a major impact on the packaging and utilization of the genome. The first is repression (and sometimes activation) of gene expression through structural changes in chromatin by the Polycomb group of chromatin regulators, which work in part through modification of histone side chains. The second is the organization of chromosomal loops by chromatin insulators, which impacts several aspects of chromosome function. These include gene expression (by either facilitating or blocking interactions between enhancers and promoters), DNA recombination and repair (by influencing which linearly distant DNA sequences are accessible to each other and which are not), chromatin compaction during mitosis and meiosis, and epigenetic maintenance of gene expression. Insulators may facilitate epigenetic maintenance by helping to keep sister chromatids aligned following DNA replication, thereby allowing histone modifications, such as those propagated by the Polycomb group, to be faithfully templated from one cellular generation to the next.
We are analyzing how long-range repression and activation occur over an entire genetic locus, even skipped (eve), and its genomic neighborhood, through the regulation of chromatin structure. The eve gene is flanked by insulators (called homie and nhomie) that functionally isolate it from neighboring genes. Along with Polycomb-group response elements, they maintain both the activated and repressed state within different developing lineages of cells. Both of these kinds of elements function in a variety of genes, and in mammals as well as in Drosophila, to regulate developmental processes such as stem cell maintenance and differentiation. Understanding the mechanisms will provide novel ways to attack cancer, which is caused in large part by mis-regulation of gene expression and chromatin structure.
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