Our long-term research on the biological significance of genomic sequences that readily adopt non-B DNA structures led us to discover a specialized sequence context in which DNA bases readily becomes unpaired under superhelical strain. We called sequences with such unusual physical properties base unpairing regions (BURs). We subsequently identified SATB1, a nuclear protein that recognizes and specifically binds in vivo to BUR DNA. During the last funding period, we uncovered a new dimension in mammalian gene regulation in which SATB1 folds chromatin into loops and simultaneously regulates a large number of genes. BURs of target gene loci are tethered onto the SATB1 protein network, which serves as an architectural platform to recruit transcriptional regulators and chromatin remodeling proteins to alter epigenetic states at target loci. Interestingly, we have observed such """"""""genome organizing"""""""" activity to be closely associated with dramatic cellular changes, such as during T cell development, T cell activation, and acquisition of aggressive cancer phenotypes. Our next goals are proposed in four aims: 1) determine the roles of Satb1 post-translational modifications on functional chromatin organization and tumorigenesis, 2) determine genome organization underlying aggressive cancer, 3) study the biological function of mobile versus immobile SATB1 populations, and 4) identify and investigate the role of novel BUR-binding proteins in ES cells. These studies, connecting nuclear architecture and chromatin dynamics, will provide a new concept in gene regulation that underlies major changes in cellular phenotypes, such as during cancer progression and cell development.

Public Health Relevance

Recent findings suggest that during cellular changes, as when stem cells differentiate or cancer cells become metastatic, global changes in gene expression occur. Such a complex, large-scale event requires proper packaging and organization of the genomic DNA. Proteins that direct this organization, therefore, play key roles in many different biological processes. We will study how these proteins function to fold DNA and coordinate proper gene expression in mammalian nuclei, identify new proteins with these functions, and investigate their roles in stem cells and cancer progression.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Okano, Paul
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Lawrence Berkeley National Laboratory
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Kitagawa, Yohko; Ohkura, Naganari; Kidani, Yujiro et al. (2017) Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. Nat Immunol 18:173-183
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
Hilde, Kathryn L; Levine, Ariel J; Hinckley, Christopher A et al. (2016) Satb2 Is Required for the Development of a Spinal Exteroceptive Microcircuit that Modulates Limb Position. Neuron 91:763-776
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
Skowronska-Krawczyk, Dorota; Ma, Qi; Schwartz, Michal et al. (2014) Required enhancer-matrin-3 network interactions for a homeodomain transcription program. Nature 514:257-61
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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