Eukaryotic chromatin is organized into loop domains, which might have both structural and functional roles such as in developmental stage- and cell type-specific gene expression and replication. It is believed that chromatin loops are anchored to the nuclear substructure (or matrix) at specific DNA regions called matrix attachment regions (MARs). SATB1 specifically binds in vivo to specific DNA sites with an ATC sequence context, which has high propensity to unwind under negative superhelical strain. These sites are referred to as base-unpairing region (BUR) and are hyper-reactive to chemical carcinogens. BURs represent a hallmark of MARs. SATB1 is a cell-type specific BUR-binding protein predominantly expressed in thymocytes. Analyses of SATB1 knockout mice showed that SATB1 is essential for proper T cell development by orchestrating spatial and temporal expression of a large number of genes in thymocytes. SATB1 actively tethers SATB1-bound sequences in vivo onto the nuclear substructure and regulates distant genes. Our recent data using SATB1 knockout mice and ES cells show that SATB1 has a regulatory role in imprinted genes, Igf2 and H19, as well as Xist, In the current proposal, we propose to 1) study the role of SATB1 in regulating imprinted Igf2 and H19 genes, 2) determine the effects of deleting an in vivo SATB1-binding sequence BUR located between Igf2 and H19 on the allele-specific expression, methylation and chromatin structure of Igf2 and H19 genes in mice, 3) examine the role of SATBI in the coordinated expression of Xist and its antisense gene Tsix, 4) determine whether BURs have a role in the chromosomal replicator function, and 5) isolate a BUR-binding protein distinct from SATB1 from ES cells possessing the activity similar to SATB1 in assembling the chromatin-remodeling complex. These experiments, using both SATB1 knockout mice and ES cells will provide important information on not only the biological function of SATB1, but also how higher order chromatin structure is organized to regulate gene expression and replication through DNA loop anchorage sequences.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA039681-21
Application #
6710687
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Okano, Paul
Project Start
1985-04-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
21
Fiscal Year
2004
Total Cost
$622,861
Indirect Cost
Name
Lawrence Berkeley National Laboratory
Department
Biology
Type
Organized Research Units
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
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Poterlowicz, Krzysztof; Yarker, Joanne L; Malashchuk, Igor et al. (2017) 5C analysis of the Epidermal Differentiation Complex locus reveals distinct chromatin interaction networks between gene-rich and gene-poor TADs in skin epithelial cells. PLoS Genet 13:e1006966
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Kondo, Motonari; Tanaka, Yuriko; Kuwabara, Taku et al. (2016) SATB1 Plays a Critical Role in Establishment of Immune Tolerance. J Immunol 196:563-72
Hao, Bingtao; Naik, Abani Kanta; Watanabe, Akiko et al. (2015) An anti-silencer- and SATB1-dependent chromatin hub regulates Rag1 and Rag2 gene expression during thymocyte development. J Exp Med 212:809-24
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Satoh, Yusuke; Yokota, Takafumi; Sudo, Takao et al. (2013) The Satb1 protein directs hematopoietic stem cell differentiation toward lymphoid lineages. Immunity 38:1105-15
Kohwi-Shigematsu, Terumi; Poterlowicz, Krzysztof; Ordinario, Ellen et al. (2013) Genome organizing function of SATB1 in tumor progression. Semin Cancer Biol 23:72-9
Balamotis, Michael A; Tamberg, Nele; Woo, Young Jae et al. (2012) Satb1 ablation alters temporal expression of immediate early genes and reduces dendritic spine density during postnatal brain development. Mol Cell Biol 32:333-47
Ordinario, Ellen; Han, Hye-Jung; Furuta, Saori et al. (2012) ATM suppresses SATB1-induced malignant progression in breast epithelial cells. PLoS One 7:e51786

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