BMC Genomics 2006, 7:42 http://www.biomedcentral.com/1471-2164/7/42 fSFeiigrgneunifritciealn3lyt emxoptriefsssdeedtegcetneedsin the promoter regions of the dif- Significant motifs detected in the promoter regions of the differentially expressed genes. The significant motifs found in the promoters of the differentially expressed genes are given along with their sequence logos and top TRANSFAC hit. Apoptosis can be induced directly by DNA damage or by cytokine signalling. The genes more highly expressed in intestinal tissue of susceptible animals also included a number that encode proteins involved in protein degradation: these are PSMD12, which encodes a non-ATPase component of the 26S proteasome subunit, UBD which encodes a ubiquitin- like protein that targets proteins for degradation and BMSC-UbP which encodes a bone marrow stromal cell derived ubiquitin-like protein [46,61,62]. Another gene which can play a role in protein degradation is SEC61B, which encodes the beta subunit of the Sec61 protein translocator, which transports proteins across the endo- plasmic reticulum. This complex is also known to play a role in retrograde transport of misfolded or degraded pro- teins back into the cytoplasm for proteasome degradation [63]. Therefore there appears to be increased protein deg- radation in the intestinal tract of the susceptible animals. In summary, a number of stress response genes appear to be induced in the intestinal tract of naïve susceptible ani- mals. How the induction of these genes is regulated is unclear at present, however, the identification of two sig- nificant motifs in the promoter regions of these genes indicated that transcription may be co-ordinately regu- lated by the BSAP or PPARG transcription factors. The role of PPARG in regulating genes involved in nematode sus- ceptibility could potentially be examined by treating ani- mals with PPARG agonists in order to modulate PPARG activation. Motifs for BSAP or PPARG binding were not Table 4: MAST results found in the promoter region of genes whose expression was not elevated in the susceptible animals, showing they are unique to these genes. Only 16 genes were more highly expressed in the intestine of the resistant animals than the susceptible animals. These genes had a variety of biological functions and the only GO term significantly associated with these genes was "cellular process". However two of genes more highly expressed in the resistant animals are vital for maintaining a functioning and healthy immune system. RAC2 plays an important role in response to pathogens as it regulates neutrophil chemotaxis and superoxide production and deficiency of RAC2 leads to impaired host defences and neutrophilia [64,65]. Deficiency of ITGB2, also known as CD18, can also lead to neutrophilia [66] and ITGB2 is also known to be important in innate immunity [67]. Two apoptosis inducing genes are more highly expressed in the intestine of the resistant animals. These genes are DAP3 and TRADD. DAP3, a proposed nucleotide binding pro- tein, is a major positive regulator of apoptosis and has been shown to be critical for anoikis [68]. TRADD encodes a tumour necrosis factor receptor adaptor pro- tein. This protein links the TNF receptor to the caspase pathway initiating apoptosis [69]. Despite a few genes with similar functions being more highly expressed in the intestine of resistant animals, no significant motifs were identified in the promoter regions of these genes indicat- ing that they may not be co-ordinately regulated at a tran- scriptional level. Alternatively, the small number of genes with significantly elevated expression provided little power to detect motifs responsible for co-ordinate regula- tion. A previous study identified genes differentially expressed between the resistant and susceptible lines in response to nematode challenge [25]. Interestingly, there were no genes that were consistently differentially expressed both pre and post-infection. However, the ubiquitin-like mod- ifier gene, UBD, was more highly expressed in the suscep- tible animals prior to infection but more highly expressed in resistant animals after infection with gastrointestinal nematodes. UBD expression is induced by the cytokines IFNγ and TNFα. Expression of TNFα is known to be induced in intestinal lymph of genetically resistant Rom- Resistant (16) Susceptible (25) Array (8809) Fisher exact score Proportion of genes with significant combination of resistant motifs Proportion of genes with significant combination of susceptible motifs 0.50 0.06 0.00 0.44 0.05 0.08 4.7 × 10-7 4.6 × 10-6 Proportion of promoter regions which contain the combination of motifs detected by MEME with P < 0.0001. Numbers in parenthesis represent the total number of genes in each group. In both cases the combination of motifs is found more frequently in the group in which it was originally identified. The significance of this is given by Fisher's exact score. Page 7 of 12 (page number not for citation purposes)