Genetic Disorders in the Arab World: United Arab Emirates

Transcriptional Regulation of Genes by ChromatinModifying Complexes and its Link to Cancer
Ahmed H Al-Marzouqi
An increasing incidence of cancer and cancer deaths occur annually. Cancer is now the second leading cause of death worldwide and is recognized as a major healthcare problem. The control of this disease benefits enormously from studying the basic mechanisms of how genes are turned on/off. We believe that research on the mechanisms of gene regulation would lead to novel therapies for cancer patients such as designing drugs that would only target specific genes responsible for cancer growth and development. Our genome is under the control of multiple mechanisms. One of them is the control of the packaging of the DNA in our cells. The packaging of eukaryotic DNA into nucleosomes inhibits the access of factors to DNA and, thus, results in the repression of important cellular processes such as transcription, replication, and recombination (van Holde, 1989). This structure, called chromatin, was linked to transcriptional regulation by genetic studies showing that mutations in histone genes affect transcription (Hirschhorn et al., 1995; Recht and Osley, 1999). In addition, in vitro transcription assays revealed that nucleosomes are able to repress basal transcription unless a preinitiation complex is assembled first (Workman et al., 1990). Many studies in the past few years have described conserved protein complexes whose function is to modulate the access of transcription factors to regulatory regions of genes relieving chromatin-mediated repression (Workman and Kingston, 1998; Vignali et al., 2000). They are classified into two categories based on their mode of action: 1. Histone acetyltransferase (HAT) and deacetylase (HDAC) complexes, which regulate the acetylation levels of amino-terminal tails of the core histones. 2. ATP-dependent complexes (such as SWI/SNF), which use the energy of ATP hydrolysis to alter and/or disrupt the structure of chromatin The action of these complexes that are able to overcome the repressive effects of chromatin is an important step in the regulation of eukaryotic gene expression. Recent studies have shown strong links between the misregulation of these protein complexes (e.g. SWI/SNF) and different type of cancers (e.g. leukemia, lymphoma, rhabdoid tumors, and breast cancer; Neely and Workman, 2002; Roberts and Orkin, 2004). A growing number of mutations in hSWI/SNF subunits, hSnf5/Ini1 and BRG1, has been found and indicates that they are tumor suppressors (DeCristofaro et al., 1999; Hendricks et al., 2004). An increasing number of tumor suppressor (Rb, BRCA1), and oncogenic (c-Myc, p53) proteins have been shown to interact with the SWI/SNF complex suggesting that it may be essential for the regulation of other tumor suppressors (Cheng et al., 1999; Bochar et al., 2000; Amati et al., 2001). The relationship between histone deacetylase (HDACs) and SWI/SNF has also been linked to human diseases, including cancer. For example, the Rb tumor suppressor protein associates with HDAC1/2 and SWI/SNF, and through this association, HDACs are believed to play a role in Rb repression of G1 regulated genes (Zhang et al., 2000; Betz et al., 2002). The overall goal of our research is to understand the basic concepts of how genes are controlled and how that affects cancer development (Hassan et al., 2001a; Hassan et al., 2001b; Hassan et al., 2002; Prochasson et al., 2003). One aim is to gain insight into the mechanisms that underlie the interactions between the different types of chromatin modifying complexes, i.e. histone deacetylase (HDAC) complexes, and the SWI/SNF ATP-dependent chromatin remodeling complex. We are investigating how these complexes communicate with each other and work together to exert their combined effect in turning genes on. It is likely that errors in the function of these complexes can result in alterations in the life cycle of the cell that would lead to the development of cancer. Thus, we are also interested in studying how chromatin misregulation contributes to cancer. 63


Research highlights and key achievements include: 1. Recruitment of chromatin-modifying complexes by acidic activators. 2. Identification of a functional link between different chromatin-modifying complexes. 3. Identification of domains in the activators that interact with SWI/SNF. 4. Identification of domain in the SWI/SNF complex that interact with nucleosomes. 5. Interaction of chromatin-modifying complexes with genes products involved in cancer development. The incidence of cancer in the UAE has been discussed in the previous chapter and the importance of studying cancer is obvious. The research to date

only provides glimpses into the mechanisms of gene regulation and cancer growth and of the drugs that can potentially be effective in treating it. The present study is the first of its kind in the field of molecular biology in the UAE that focuses on the mechanisms of gene regulation and cancer development. With collaborations with leading scientists around the world, we are bringing new technology and know-how to conduct cutting-edge basic research. This opens great opportunity for local students to participate and learn how to conduct research in this field. Through these studies we hope that broad horizons for further research in cancer and other common disorders in the UAE followed by clinical trials of some drugs will be opened.


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