Overall, more unique orthologs (~ 6 ×) were expressed in the mouse duodenal epithelia (1649 orthologs) compared to the rat (259 orthologs). Cross-species comparison of the jejunal gene expression identified similar numbers of unique differentially expressed orthologs (3782 rat and 3334 mouse) CHIR-99021 manufacturer (Fig. 5D). As observed in the duodenum, overlapping orthologs increased from 1576 to 3864 genes with reduced stringency (Figs. 5E–F). Unlike the duodenum, the number of species-specific differentially expressed genes was comparable (971 rat vs. 705 mouse). Hierarchical clustering
of the duodenal (Fig. 6A) and jejunal (Fig. 6B) overlapping orthologs revealed that at ≤ 14 mg/L SDD clustering was more random. In contrast, differential gene expression at 60–520 mg/L SDD clustered according to species. Overall, the dose-dependent induction/repression was consistent between mice
and rats. However, divergently regulated clusters were also identified (Supplementary Fig. S3A). Cross-species analysis of day 91 duodenal responses identified 1504 and 3484 differentially expressed unique orthologs for the rat and mouse, respectively (Fig. 7A). Comparative analysis identified that 811 (|fold change| > 1.5, P1(t) > 0.999) and 2536 (|fold change| > 1.2, P1(t) > 0.9) orthologs overlapped between the species. The mouse duodenal epithelia expressed more www.selleckchem.com/products/sotrastaurin-aeb071.html (~ 5 ×) non-overlapping unique orthologs compared to rat following 90 days of SDD exposure ( Figs. 7B–C). Similar comparisons learn more of jejunal differential gene expression identified 1305 rat and 3620 mouse orthologs of which 729 were expressed in both species ( Fig. 7D). Using relaxed criteria, the overlap was comparable to the duodenal orthologs at day 91 (2772 jejunal orthologs in Figs. 7E–F). Hierarchical clustering of overlapping duodenal and jejunal orthologs again showed species-specific clustering at higher doses ( Figs. 8A–B, Supplementary
Fig. S3B). Correlation analysis indicates that 81% of the overlapping differentially expressed duodenal orthologs exhibit similar patterns at day 91 (Fig. 9A, Supplementary Fig. S4). However, several divergently (induced in one species, repressed in other) expressed orthologs associated with the immune response (Ccl24, C3), ion transport (Slc25a25), and growth factor/cytokine signaling (Areg) ( Table 2) were identified and verified by QRT-PCR ( Fig. 9B, Supplementary Fig. S5). Approximately, 61% (2536 out of 4177) of all orthologs were differentially expressed in the rat and mouse duodena. However, 1392 orthologs exhibited mouse-specific differential expression compared to only 249 in the rat (Fig. 7C). This qualitative (i.e. different genes/orthologs) and quantitative (number of species-specific differentially expressed orthologs) difference may contribute to the species-specific tumor outcomes. Hierarchical clustering of species-specific expressions revealed most genes exhibited weaker potency and efficacy in the rat compared to the mouse (Supplementary Fig. Fig. S6).