Progression through developmental stages requires complex interactions of transcription factors and regulatory elements to achieve correct temporal and spatial patterns of requisite gene expression. Biochemical and genetic studies have implicated epigenetic modifications of chromatin structure as an important mechanism in regulation of gene transcription. Alteration of nucleosome conformation and/or position (termed chromatin remodeling) within gene regulatory elements serves to promote or restrict gene expression through regulating accessibility of trans-acting transcription factors. Mechanistically, modification of local chromatin structure is achieved, in part, through the activity of multi-subunit protein complexes that utilize the energy of ATP hydrolysis to disrupt nucleosome conformation and position. One important class of mammalian ATP- dependent nucleosome remodelers is that of the SWI/SNF-related family, which consists of large, multi-protein complexes that utilize either brahma (BRM) or brahma-related gene 1 (BRG1) as the catalytic subunit. Biochemical studies on the human SWI-SNF-related complexes and its yeast counterpart have demonstrated the ability of these complexes to disrupt histone-DNA contacts and reposition nucleosomes in an ATP-dependent manner. Consequently, the SWI/SNF family of complexes functions to render nucleosomal DNA more accessible to transcription factors and restriction enzymes. Mammalian SWI/SNF complexes can be grouped into two major subfamilies, BAF (Brahma-related-gene 1 (BRG1)-associated factor) and PBAF (polybromo- associated BAF). Although the BAF/PBAF complexes share many common subunits;they are distinguishable by the presence of four unique subunits. Although gene-targeting studies in the mouse have implicated SWI/SNF-related complexes in developmental processes, no studies have been done to distinguish the in vivo functional differences between the subfamilies of complexes. To test the hypothesis that the unique subunits are essential for mediating distinct BAF/PBAF cofactor activities at select sites on chromatin in a gene- or cell type-specific manner, a series of novel genetic experiments in mouse are proposed to distinguish complex function by examining phenotype at different times and in various tissue types during development. Public Health Relevance: Biochemical studies on chromatin remodeling complexes have demonstrated their ability to disrupt histone- DNA contacts and reposition nucleosomes. Consequently, these complexes are critical in regulating global gene expression. Genetic experiments are proposed to elucidate the biological specificity of these complexes and the abnormal outcomes that lead to disease states when inappropriately expressed.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD036655-14
Application #
8326626
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Coulombe, James N
Project Start
1999-01-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
14
Fiscal Year
2012
Total Cost
$298,901
Indirect Cost
$96,941
Name
University of North Carolina Chapel Hill
Department
Genetics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Chandler, Ronald L; Magnuson, Terry (2016) The SWI/SNF BAF-A complex is essential for neural crest development. Dev Biol 411:15-24
Serber, Daniel W; Runge, John S; Menon, Debashish U et al. (2016) The Mouse INO80 Chromatin-Remodeling Complex Is an Essential Meiotic Factor for Spermatogenesis. Biol Reprod 94:8
Katz, David M; Bird, Adrian; Coenraads, Monica et al. (2016) Rett Syndrome: Crossing the Threshold to Clinical Translation. Trends Neurosci 39:100-13
Chandler, Ronald L; Damrauer, Jeffrey S; Raab, Jesse R et al. (2015) Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling. Nat Commun 6:6118
Chandler, Ronald L; Raab, Jesse R; Vernon, Mike et al. (2015) Global gene expression profiling of a mouse model of ovarian clear cell carcinoma caused by ARID1A and PIK3CA mutations implicates a role for inflammatory cytokine signaling. Genom Data 5:329-32
Raab, Jesse R; Resnick, Samuel; Magnuson, Terry (2015) Genome-Wide Transcriptional Regulation Mediated by Biochemically Distinct SWI/SNF Complexes. PLoS Genet 11:e1005748
Chandler, Ronald L; Zhang, Ying; Magnuson, Terry et al. (2014) Characterization of a Brg1ýýhypomorphic allele demonstrates that genetic and biochemical activity are tightly correlated. Epigenetics 9:249-56
Chandler, Ronald L; Brennan, Jennifer; Schisler, Jonathan C et al. (2013) ARID1a-DNA interactions are required for promoter occupancy by SWI/SNF. Mol Cell Biol 33:265-80
Kim, Yuna; Fedoriw, Andrew M; Magnuson, Terry (2012) An essential role for a mammalian SWI/SNF chromatin-remodeling complex during male meiosis. Development 139:1133-40
Fedoriw, Andrew M; Starmer, Joshua; Yee, Della et al. (2012) Nucleolar association and transcriptional inhibition through 5S rDNA in mammals. PLoS Genet 8:e1002468

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