This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The gypsy chromatin insulator of Drosophila melanogaster is the best understood insulator to date. It is a DNA sequence containing 12 copies of a binding site for the DNA-binding protein Suppressor of Hairy-wing [Su(Hw)] which recruits other insulator proteins to organize the insulator complex. We reported that the centrosomal protein CP190 is an essential component of the gypsy insulator. It was recently discovered that CP190 is also present in the Fab-8 insulator complex which depends on the DNA-binding protein CTCF instead of Su(Hw). CTCF has important roles on epigenetic control of gene expression and is a human tumor suppressor. Current evidence indicates that CP190 has essential functions in multiple types of insulators and may be involved in genetic imprinting and tumor suppression. The main goals of this proposal are to: 1) Determine the function of CP190's protein sub-domains in gypsy and Fab-8 insulator complexes;2) Identify the target DNA sequences of CP190's zinc fingers;3) Identify additional chromatin insulator components by cloning two novel insulator mutations. The proposed studies will investigate a fundamental question concerning chromatin organization and the regulation of gene expression in the cell nucleus. We will gain insights into the molecular mechanisms through which chromatin insulators regulate gene expression, and more generally, chromatin structure and organization of the cell nucleus. Currently drugs are being tested that target chromatin regulators as a therapeutic approach to cancers and to untreatable neurological conditions like Huntington disease. More detailed knowledge of the basic mechanisms of chromatin insulators could lead to better design of new treatments and may lead to discovery of new drug targets.
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