Importance of Identifying Transcriptional Regulatory Networks in Toxicogenomics

Administered in critical doses, drugs and chemicals can damage organs and tissues by turning numerous genes on or off. Changes in the expression patterns of target genes indicate toxic action and are manifested as multiple toxicological endpoints detectable by transcriptome analysis. Microarray technology allows measuring transcriptional modulation of thousands of genes after exposure to xenobiotics. Induction or repression of genes is mediated by an altered protein-DNA binding pattern of nuclear transcription factors (TFs). TFs are regulatory proteins that bind to the promoters or enhancers of their respective target genes and thereby affect gene expression and potentially lead to dysfunction of target organs. Approximately 2000 TFs [1, 2] are responsible for controlling the entire gene expression from development and differentiation to metabolic functions. A major challenge in genomic research today involves identifying more of their respective target genes.

Regulation of gene transcription is a multifactorial process. TFs bind to a specific DNA sequence in the control region of a gene and interact with so-called general basal factors to recruit RNA polymerase II to the transcription start site of a gene. These proteins together form a multiprotein complex that permits regulated mRNA synthesis [3]. Initiation of transcription is frequently the result of binding of many different TFs to cognate DNA binding sites, which enables combinatorial control of gene expression. An additional level of complexity is provided by protein-protein interactions between TFs and cofactors and between synergistically acting TFs [4]. The activation of a gene requires accessibility of TFs, cofactors, and basal factors to the regulatory region. Chromatin remodelling complexes change chromatin structure by altering DNA-histone contacts within a nucleosome and make regions of the genome accessible to target transcription factor binding [5]. Several transcriptional coac-tivators contribute to chromatin remodelling [6].

Involvement of different kinds of TFs and cofactors in specific target gene regulation allows the integration of several signalling pathways. Identifying the target genes for specific TFs as well as discovering the crosstalk mechanism involved will lead to understanding the transcriptional network.

The liver is the first organ that encounters toxins that have been absorbed through the intestines. One of the major roles of the liver is detoxification and metabolism of xenobiotics [7]. Particularly with regard to predicting the toxic action of xenobiotic compounds, identification of all targets of liver-specific TFs (for review see Schrem et al. [8, 9]) would constitute great progress in toxicogenomics. Substances could be grouped mechanistically by targeting the same TF pattern, and prediction of toxic action would then be possible through analyses of changes in TF binding prior to observable damage to the tissue.

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