Nucleosomes and other components of chromatin act as potent repressers of eukaryotic transcription by blocking the access of transcription factors and other regulatory proteins to DNA. Chromatin repression is regulated via two general mechanisms: ATP-dependent chromatin remodeling and the covalent modification of nucleosomal histones. The disruption of these processes leads to a variety of human diseases, including cancer. In spite of tremendous progress toward determining the mechanism of action of chromatin- remodeling factors and histone-modifying enzymes, much remains to be learned about their roles in eukaryotic transcription and human disease. Recent studies have suggested that chromatin-remodeling factors can regulate higher-order chromatin structure, but their role in this process remains poorly understood. To address these important issues, our laboratory uses Drosophila melanogaster as a model system to study three different chromatin-remodeling factors: BRM, KIS-L and ISWI. We recently found that BRM and KIS-L play global roles in transcription by RNA Polymerase II. To determine the precise roles of BRM and KIS-L in transcription, we will characterize defects resulting from their loss of function and map the regions of active genes with which they interact in vivo. We will also examine whether the site-specific methylation of histone tails affects the ability of BRM or KIS-L to interact with their chromatin substrates. Unlike BRM and KIS-L, ISWI plays a global role in chromatin compaction and transcriptional repression, possibly by promoting the association of the linker histone H1 with chromatin. To test this hypothesis, we will characterize defects in chromosome structure resulting from the loss of ISWI function and investigate the consequences of reducing histone H1 function using RNAi and engineered dominant-negative mutations. To identify other factors involved in the regulation of higher-order chromatin structure, we will screen for mutations that cause chromosome defects similar to those observed in ISWI mutants. By simultaneously studying three different chromatin-remodeling factors in a single organism, we will gain a much better understanding of their roles in transcription and other processes. Counterparts of Drosophila chromatin-remodeling factors - including BRM, KIS-L and ISWI - are present in humans, where they play highly conserved roles in gene expression and development. Mutations in these factors are associated with a variety of cancers, including rhabdoid tumors, breast cancer, and leukemias. Our studies of chromatin-remodeling factors in a genetic model organism should therefore shed light on the molecular mechanisms underlying these human cancers and other diseases. ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular Genetics B Study Section (MGB)
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Carter, Anthony D
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University of California Santa Cruz
Schools of Arts and Sciences
Santa Cruz
United States
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Siriaco, Giorgia; Deuring, Renate; Mawla, Gina D et al. (2015) A novel approach for studying histone H1 function in vivo. Genetics 200:29-33
Kingston, Robert E; Tamkun, John W (2014) Transcriptional regulation by trithorax-group proteins. Cold Spring Harb Perspect Biol 6:a019349
Dorighi, Kristel M; Tamkun, John W (2013) The trithorax group proteins Kismet and ASH1 promote H3K36 dimethylation to counteract Polycomb group repression in Drosophila. Development 140:4182-92
Siriaco, Giorgia; Tamkun, John W (2013) A histone timer for zygotic genome activation. Dev Cell 26:558-9
Fasulo, Barbara; Deuring, Renate; Murawska, Magdalena et al. (2012) The Drosophila MI-2 chromatin-remodeling factor regulates higher-order chromatin structure and cohesin dynamics in vivo. PLoS Genet 8:e1002878
Siriaco, Giorgia; Deuring, Renate; Chioda, Mariacristina et al. (2009) Drosophila ISWI regulates the association of histone H1 with interphase chromosomes in vivo. Genetics 182:661-9
Srinivasan, Shrividhya; Dorighi, Kristel M; Tamkun, John W (2008) Drosophila Kismet regulates histone H3 lysine 27 methylation and early elongation by RNA polymerase II. PLoS Genet 4:e1000217
Burgio, Giosalba; La Rocca, Gaspare; Sala, Anna et al. (2008) Genetic identification of a network of factors that functionally interact with the nucleosome remodeling ATPase ISWI. PLoS Genet 4:e1000089
Corona, Davide F V; Siriaco, Giorgia; Armstrong, Jennifer A et al. (2007) ISWI regulates higher-order chromatin structure and histone H1 assembly in vivo. PLoS Biol 5:e232
Srinivasan, Shrividhya; Armstrong, Jennifer A; Deuring, Renate et al. (2005) The Drosophila trithorax group protein Kismet facilitates an early step in transcriptional elongation by RNA Polymerase II. Development 132:1623-35

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