Terumi Kohwi-Shigematsu, PhD

For many years, I have led the research investigating how the mammalian genome is functionally organized in nuclei so that genes are appropriately and efficiently activated or repressed to elicit specific biological functions.  This research began when we first identified a unique genomic sequence context, which is highly potentiated for base unpairing (BURs: base unpairing regions). Subsequently, my lab cloned SATB1, which encodes a nuclear protein that specifically binds BURs when they are double-stranded. We found that SATB1 has a unique cage-like distribution in thymocyte nuclei and folds genomic DNA into three-dimensional configurations by tethering BURs onto its cage structure. Such higher-order chromatin structure is tightly linked to spatial and temporal gene regulation: SATB1 provides a landing platform for the assembly of chromatin remodeling/modifying complexes with the anchored genomic loci, thereby regulating a cell-type specific epigenetic program and expression of a large cohort of genes. Thus, we introduced a new concept in gene regulation in which SATB1 functions as a “genome organizer” that generates a functional nuclear architecture, which we refer to as ‘the SATB1 gene network,’ as it establishes a regulatory network of gene expression. We found that SATB1 promotes changes in cell phenotypes such as during T cell activation, development of multiple cell lineages, and cancer metastasis.  My research group developed multiple methods (i.e. ChIP-3C, ChIP-4Cseq, and 4C-seq) to study the Satb1-mediated chromatin organization in mammalian cells, such as chromatin looping formed by intra- and inter-chromosomal interactions as part of the gene regulatory network.  We found that SATB1 is a critical factor for promoting metastasis in breast cancer and for chemoresistance.  This SATB1 activity and the high prognostic significance of this protein have since been validated by others for 20 different types of cancers. My laboratory has moved to University of California San Francisco (UCSF) in September, 2015.  We expanded our studies on SATB1 function in cancer progression at UCSF and identified a specific subpopulation of SATB1 proteins characterized by a unique biochemical property is specifically present in aggressive, but not in non-aggressive epithelial cancers. Thus, we have a unique opportunity to study further about the key roles of the genome organizer in recurrence and chemoresistance of these cancers. Besides SATB1, we have identified a new genome organizer in embryonic stem cells responsible for pluripotency.  We are actively studying the function of this nuclear factor in detail.