All of the processes necessary for the survival of a living system hinge on its ability to store and read the genetic information encoded in its DNA. The packaging a long genome into the eukaryotic nucleus or prokaryotic nucleoid is complicated by the necessity of maintaining the accessibility of the DNA for genetic processing. The binding of multiple proteins to DNA plays an important role in reading and compacting the genome. Many regulatory proteins bind two or more widely separated sites along DNA, forcing the intervening sequence into a loop. Other architectural proteins deform the DNA at isolated sites of contact while concomitantly wrapping DNA on their surfaces. The complex interplay of DNA and these different types of proteins is one of the most exciting areas of contemporary biology. For example, the deletion of architectural proteins in E. coli cells perturbs the repression of genes controlled by the Lac repressor and chemical modifications of the histone proteins in eukaryotes, so-called epigenetic markers, affect a host of cellular processes. Although there is a large literature on protein- mediated DNA looping, there is no systematic understanding of how non-specific architectural proteins contribute to the formation of loops and how the structures of loop-mediating proteins like LacR control looping and gene repression. Several interrelated problems complicate the modeling of loops. First, the in vivo structures of both the bacterial nucleoid and chromatin are unknown. Second, since these loops contain too many constituents to be modeled at the atomic level, simplifications must be introduced. Third, popular approaches used to model DNA looping have important deficiencies. To address these needs, we propose to (i) establish methodologies to model long, protein-decorated DNA chains at a 'realistic'level and characterize the topology of the simulated structures, (ii) establish the role of architectural and regulatory proteins found in the bacterial nucleoid on the spatial organization and expression of genes, and (iii) establish the role of nucleosome structure and deformation on the organization and expression of genes in a model system. Aside from the fundamental importance to an understanding of biology, knowledge of the interplay between local and large-scale biomolecular structure and genetic function could transform life-science technologies. That is, if certain environmental pressures perturb genomic structure and switch genes on or off, then perhaps one might be able to engineer such changes in an organism and correct diseased states or optimize production of desired products.
The proposed studies of DNA in the presence of multiple proteins will extend our knowledge of how the three-dimensional packaging of DNA in the cells of different organisms contributes to the processing of genetic information. Aside from fundamental understanding of biology, this information has the potential to transform life-science technologies. That is, if certain environmental pressures perturb genomic structure and switch genes on or off, then perhaps one might be able to engineer such changes in an organism and correct diseased states or optimize production of desired products.
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