MERIT Award Recipient: Terumi Kohwi-Shigematsu, Ph.D.
Non B DNA Structure with Chemical Carcinogens
Chromosomal DNA fiber is packaged in an organized manner inside cells' nuclei, so that only a subset of the genome is expressed in any given cell type and at any given time. An important element of DNA packaging involves folding into loop domains. It is believed that chromosomal DNA loops are anchored to the nuclear substructure (or matrix) at specific DNA regions called matrix attachment regions (MARs). However, relatively little is known about the proteins that play a role in organizing chromosomal DNA into functional loop domains. The Kohwi-Shigematsu laboratory has identified one such protein, SATB1, which is a cell type-restricted protein, predominantly expressed in thymocytes, activated T cells, and some precursor/progenitor cells. The absence of the SATB1 protein in mice causes the dysregulation of numerous genes in thymocytes, resulting in impaired T cell development.
SATB1 specifically recognizes a particular DNA region (base unpairing region; BUR) within MARs, which is highly prone to DNA unwinding and hyper-reactive to chemical carcinogens. BURs represent a hallmark of MARs. SATB1 exhibits a dense, chicken wire-like network distribution in nuclei, circumscribing heterochromatin regions. SATB1 actively folds chromatin into loop domains by tethering BUR DNA sequences to the SATB1 network to regulate numerous genes up to 50,000 DNA base pairs from the SATB1 binding sites. In addition to serving as docking sites for chromosomal fibers at their loop bases, the SATB1 network provides landing platforms for recruiting several chromatin-remodeling enzymes, such as the NURD complex and CHRAC/ACF complex, to modulate large chromatin domains. SATB1 targets these chromatin-remodeling complexes to specific sites in the genome to regulate cell type-specific genes. SATB1 thus provides the first example of how a protein can regulate expression of hundreds of genes by linking transcriptional activity of these genes to nuclear organization.
Dr. Kohwi-Shigematsu's laboratory is particularly interested in the effects that SATB1 has on the expression of cell type-specific genes and "imprinted" genes, which are expressed only from the maternally-inherited chromosome or only from the paternally-inherited chromosome. Imprinted genes provide an excellent model for understanding how genes are regulated. Also, these genes often control normal cell and tissue differentiation, and their dysregulation may contribute to the initiation and/or progression of cancer. Dr. Kohwi-Shigematsu and coworkers have also identified proteins with DNA-binding specificity similar to that of SATB1 in stem cells, neurons, and some cancer cells. They are in the process of understanding these DNA-binding proteins' roles in these cells. This series of studies will reveal fundamental mechanisms for how genes are regulated (or dysregulated) at the level of large-scale chromatin structure during differentiation and tumorigenesis.