| Summary: | <p>Abstract</p> <p>Background</p> <p>Recently, we identified <it>cysteine-rich with EGF-like domains 2 </it>(<it>CRELD2</it>) as a novel endoplasmic reticulum (ER) stress-inducible gene and characterized its transcriptional regulation by ATF6 under ER stress conditions. Interestingly, the <it>CRELD2 </it>and <it>asparagine-linked glycosylation 12 homolog </it>(<it>ALG12</it>) genes are arranged as a bidirectional (head-to-head) gene pair and are separated by less than 400 bp. In this study, we characterized the transcriptional regulation of the mouse <it>CRELD2 </it>and <it>ALG12 </it>genes that is mediated by a common bidirectional promoter.</p> <p>Results</p> <p>This short intergenic region contains an ER stress response element (ERSE) sequence and is well conserved among the human, rat and mouse genomes. Microarray analysis revealed that <it>CRELD2 </it>and <it>ALG12 </it>mRNAs were induced in Neuro2a cells by treatment with thapsigargin (Tg), an ER stress inducer, in a time-dependent manner. Other ER stress inducers, tunicamycin and brefeldin A, also increased the expression of these two mRNAs in Neuro2a cells. We then tested for the possible involvement of the ERSE motif and other regulatory sites of the intergenic region in the transcriptional regulation of the mouse <it>CRELD2 </it>and <it>ALG12 </it>genes by using variants of the bidirectional reporter construct. With regards to the promoter activities of the <it>CRELD2</it>-<it>ALG12 </it>gene pair, the entire intergenic region hardly responded to Tg, whereas the <it>CRELD2 </it>promoter constructs of the proximal region containing the ERSE motif showed a marked responsiveness to Tg. The same ERSE motif of <it>ALG12 </it>gene in the opposite direction was less responsive to Tg. The direction and the distance of this motif from each transcriptional start site, however, has no impact on the responsiveness of either gene to Tg treatment. Additionally, we found three putative sequences in the intergenic region that antagonize the ERSE-mediated transcriptional activation.</p> <p>Conclusions</p> <p>These results show that the mouse <it>CRELD2 </it>and <it>ALG12 </it>genes are arranged as a unique bidirectional gene pair and that they may be regulated by the combined interactions between ATF6 and multiple other transcriptional factors. Our studies provide new insights into the complex transcriptional regulation of bidirectional gene pairs under pathophysiological conditions.</p>
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