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-subunt 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. 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 different ARID DNA binding subunits. Preliminary data suggest that these variant complexes exist in a delicate balance with each other, and upon loss of one complex, large-scale reorganization of the chromatin-remodeling machinery occurs. A series of experiments are proposed to study how these complexes interact with one another and with the genome on a global scale. Such an approach is critical to address how the balance of chromatin remodeling complexes contributes to a stable system of gene expression and how loss of this balance contributes to developmental abnormalities and disease.

Public Health Relevance

Exome sequencing studies have identified numerous subunits of the SWI/SNF family of chromatin remodelers as potential driver mutations in developmental abnormalities and cancer. We are proposing that chromatin-remodeling complexes exist in a delicate balance with each other, and upon loss of one complex, large-scale reorganization of the chromatin-remodeling machinery occurs. We hypothesize that this has profound effects for proper gene regulation. Rather than studying a single chromatin-remodeling complex at a small set of genes, we are proposing to study how these complexes interact with one another within the same cell and with the genome on a global scale. Such an approach is critical to address how the balance of chromatin remodeling complexes contributes to a stable system of gene expression and how loss of this balance contributes to developmental abnormalities and disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01HD036655-15A1
Application #
8691568
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Coulombe, James N
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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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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