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Background  Recently, we identified   c ysteine- r ich with  E GF- l ike  d omains 2  ( CRELD2 ) as a novel endoplasmic reticulum (ER) stress-inducible gene and characterized its transcriptional regulation by ATF6 under ER stress conditions. Interestingly, the  CRELD2  and   a sparagine- l inked  g lycosylation 12 homolog  ( ALG12 ) 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  CRELD2  and  ALG12  genes that is mediated by a common bidirectional promoter.    Results  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  CRELD2  and  ALG12  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  CRELD2  and  ALG12  genes by using variants of the bidirectional reporter construct. With regards to the promoter activities of the  CRELD2 - ALG12  gene pair, the entire intergenic region hardly responded to Tg, whereas the  CRELD2  promoter constructs of the proximal region containing the ERSE motif showed a marked responsiveness to Tg. The same ERSE motif of  ALG12  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.    Conclusions  These results show that the mouse  CRELD2  and  ALG12  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.

Role of an ER stress response element in regulating the bidirectional promoter of the mouse CRELD2 - ALG12 gene pair