Analysis of Promoters of Ah Receptor Regulated Genes

The aryl hydrocarbon receptor (AhR) is a ligand-activated nuclear transcription factor that mediates responses to a variety of toxins. Among them are halogenated aromatic toxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polynuclear aromatic hydrocarbons, combustion products, and numerous phytochemicals such as flavonoids and indole-3-carbinol (I3C). Experimental data obtained by RT-PCR on AhR-respon-sive genes were investigated with the CompositeModuleFinder to reveal TF binding sites and their specific combinations related to AhR-responsiveness (Kel et al., 2004b).

Several matrices in various combinations were revealed in the 5' regions of these genes. Among the most discriminative matrices were those for the following TFs:

HNF1, AhR, GR, OCT, and C/EBP. Among the most prominent matrix pairs selected by the algorithm were HNF-1/Sp-1 and AP-1/NF-1 for the maximum distance R = 100 bp; E2F/NF-1, AhR/Myb, HNF3/NFY, HNF6/NF-kB, and Sp-1/Myb for the maximum distance R = 50 bp; and HNF-1/GR for the maximum distance R = 40 bp. It was interesting to observe that not all matrices found individually were also found in pairs and that not only discriminating individual TFs appear in pairs. This gives

Tab. 12.5 Composite module CMAhR constructed for the (-2000 +2000) set of AhR-regulated promoters.

Factor or pair offactors (distance)


IRF/SRY (50) HNF3/SRY (50) AP1/NF1 (100) SP1/MYB (50) GR/HNF1 (40) AHR/MYB (50) HNF1/SP1 (100) E2F/ROR (100) AHR/CREB (100)

0.105086 0.084289 0.077050 -0.169821 0.213636 0.164787 0.149481 0.138358 0.137571 0.124308 0.110810 -0.115593 -0.0

Fig. 12.7 Discrimination between (-2000+2000) promoters (light gray) and background promoters from chromosome 21 (PR: -2000 +2000) (dark gray) by the composite module CMAhR. The composite module score FCM is given on the abscissa.

us an additional idea of the composite structure of the promoters being studied. In Table 12.5 we present a combination of individual matrices and matrix pairs that give one of the best discriminations of the set of promoters of AhR-regulated genes (-2000 +2000) from other promoters. We call this set of matrices AhR-associated composite regulatory modules (CMAhR) of the promoters being studied.

As can be seen in Figure 12.7, the distribution of the composite module scores Fcm is clearly different in these two sets of promoters (T-test value is 12.12, p value = 1.7 10-28). The AhR-responsive promoters have clearly higher FCM scores than the background promoters.

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