Terumi Kohwi-Shigematsu Project
The primary DNA sequence of the human genome, containing over 3 billion base pairs, has been determined. However, a key question about genetic information still remains: how the cell nucleus manages precisely to fold approximately 2 m of DNA, to fit into and the small nuclear volume (approximately 10μm diameter), yet still access the sequence information. The long DNA fiber wrapped around histone protein cores is folded in a multi-step fashion into higher-order chromatin structures. These chromatin structures must have fully functional chromatin architecture, allowing the sequence information to be utilized to establish gene expression programs in a cell-type, developmental stage- or stimulation-specific manner. To understand human development and diseases, it is essential to understand the mechanism underlying functional 3-dimensional folding of chromatin into loops, allowing interactions of distant genes and regulatory sequences in the nuclear space.
Terumi Kohwi-Shigematsu’s lab has been studying critical DNA elements in the linear DNA sequences that serve as genomic landmarks for folding chromatin into loop structures. The group identified specialized DNA sequences, characterized by a unique physical property with an exceptionally high unwinding potential. Under negative superhelical strain, nucleotides of these sequences become continuously unpaired. These sequences (less than 100 base pair in length), identified by specific chemical probes though not by consensus sequences, were named base-unpairing regions (BURs). BURs are found throughout the genome, enriched in gene-rich regions and not found in coding sequences. These studies on BURs led to a subsequent discovery of a protein, SATB1 (Special AT-rich binding protein 1), which binds specifically to BURs when they are in the double-stranded form, recognizing their altered phosphate backbone structure.
Through studying the biological roles of SATB1, Terumi’s group introduced a concept of “genome organizer” in gene regulation, in which the SATB1 nuclear architecture (i.e., the SATB1 cage-like network) plays a crucial role in regulating the three-dimensional folding of chromatin, bringing distal genes and regulatory regions together. Furthermore, SATB1 recruits epigenetic and transcriptional factors to specific genomic loci to establish region-specific epigenetic modifications. With these activities, SATB1 is able to spatially and temporally regulate chromatin architecture to reprogram gene expression profiles when cells undergo phenotypic changes. For instance, Terumi’s group found SATB1’s genomic organizing activity to be essential in T cell activation and breast cancer metastasis. To date, SATB1’s role in promoting metastasis has been verified by many other groups, in approximately 40 different cancer types. In collaboration with other groups, SATB1’s role in cell differentiation has also been demonstrated.
Proteins that specifically recognize and bind to BURs are not limited to SATB1, and Terumi’s research team has now begun to investigate genome organizers that might be required for embryonic stem cell properties and neuronal function.
Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment.
Nat. Immunol. 2017 Feb;18(2):173-183
Satb2 Is Required for the Development of a Spinal Exteroceptive Microcircuit that Modulates Limb Position.
Neuron 2016 Aug;91(4):763-776
SATB1 Plays a Critical Role in Establishment of Immune Tolerance.
J. Immunol. 2016 Jan;196(2):563-72
An anti-silencer- and SATB1-dependent chromatin hub regulates Rag1 and Rag2 gene expression during thymocyte development.
J. Exp. Med. 2015 May;212(5):809-24
Required enhancer-matrin-3 network interactions for a homeodomain transcription program.
Nature 2014 Oct;514(7521):257-61
The Satb1 protein directs hematopoietic stem cell differentiation toward lymphoid lineages.
Immunity 2013 Jun;38(6):1105-15
Genome organizing function of SATB1 in tumor progression.
Semin. Cancer Biol. 2013 Apr;23(2):72-9
A network of genetic repression and derepression specifies projection fates in the developing neocortex.
Proc. Natl. Acad. Sci. U.S.A. 2012 Nov;109(47):19071-8
ATM suppresses SATB1-induced malignant progression in breast epithelial cells.
PLoS ONE 2012 ;7(12):e51786
SATB1-mediated functional packaging of chromatin into loops.
Methods 2012 Nov;58(3):243-54
Satb1 ablation alters temporal expression of immediate early genes and reduces dendritic spine density during postnatal brain development.
Mol. Cell. Biol. 2012 Jan;32(2):333-47
p63 regulates Satb1 to control tissue-specific chromatin remodeling during development of the epidermis.
J. Cell Biol. 2011 Sep;194(6):825-39
Satb1 and Satb2 regulate embryonic stem cell differentiation and Nanog expression.
Genes Dev. 2009 Nov;23(22):2625-38
SATB1 defines the developmental context for gene silencing by Xist in lymphoma and embryonic cells.
Dev. Cell 2009 Apr;16(4):507-16
SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis.
Nature 2008 Mar;452(7184):187-93
SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes.
Nat. Genet. 2006 Nov;38(11):1278-88
A nuclear targeting determinant for SATB1, a genome organizer in the T cell lineage.
Cell Cycle 2005 Aug;4(8):1099-106
Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome.
Nat. Genet. 2005 Jan;37(1):31-40
Tissue-specific nuclear architecture and gene expression regulated by SATB1.
Nat. Genet. 2003 May;34(1):42-51
SATB1 targets chromatin remodelling to regulate genes over long distances.
Nature 2002 Oct;419(6907):641-5
Terumi Kohwi-Shigematsu, Ph.D. has been awarded the NCI MERIT award 2011