Understanding the way in which the immense amount of DNA contained in a eucaryotic nucleus is organized is one of the greatest challenges in molecular biology. This organization must ensure a mechanism for the orderly progress of DNA replication in each cell cycle and for the highly orchestrated expression of specific genes throughout development. One level of organization of the DNA can be described as consisting of topologically constrained domains (loops), each containing approximately 30,000-100,000 base pairs of DNA, anchored to a nuclear skeleton or matrix. Our initial studies have produced several intriguing observations relating the organization of DNA into loops, the nuclear matrix, and the processes of DNA replication and gene expression. In the experiments proposed in this application, we wish to test three hypotheses based on these initial data. These hypotheses are concerned, respectively, with the following ideas: (i) specific sequences within loop domains serve as their anchorage sites; the anchorage sites serve to non-randomly organize the DNA in a nucleus into discrete domains; (ii) transcriptional activation of a loop domain results in a special arrangement of DNA with respect to the structural components at its base; this arrangement of DNA with respect to the structural components at its base; this arrangement is envisaged as part of a structural network mediating the transcription of genes and the processing and transport of the genes' products; (iii) dramatic changes in the loop domains occur during embryonic development; these changes mirror those that occur in replicons. Each of these hypotheses will be rigorously tested using biochemical and morphological techniques developed in our laboratory over the past three years.

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National Cancer Institute (NCI)
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Johns Hopkins University
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