Chromatin structure and architecture. DNA within the cell nucleus is packaged into chromatin and a variety of models presently describe the structure of the condensed 30 nm chromatin fiber thought to exist in vivo. We are specifically interested in understanding the organization of DNA within condensed chromatin, as well as the topological constraints imposed on the higher order organization imposed by organizing proteins such as CTCF. Accordingly, we are developing high resolution chromosome capture conformation assays utilizing in vitro model systems and native chromatin fragments, such as the previously studied condensed heterochromatin flanked by the developmentally regulated folate receptor and beta-globin genes. These studies will allow us to better understand the structure of the 30 nm chromatin fiber in vivo, thus providing insight in the relations between chromatin structure and essential processes such as gene expression and DNA replication. Macromolecular assemblies. In collaboration with members of the Laboratory of Molecular Biology, and others, protein and protein-nucleic acid assemblies have been characterized in terms of their shape, stoichiometry and affinity of interaction using hydrodynamic methods. These studies complement current biochemical, structural and physiological investigations. An example is provided in recently published work carried out in collaboration with Dr. Appella where we characterized peptide nucleic acid nanoscaffolds used for the assembly of multivalent integrin antagonists. Specifically, we showed that five 12-base peptide nucleic acids (PNA) decorated with the integrin antagonist formed a stable complex with a 60-base complementary single stranded DNA. In this manner we have not only validated the synthetic strategy utilized for the design of programmable multivalent displays but also confirmed the stability of the complex (Englund et al., 2012).
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