In Vivo Regulation of Grp78/BiP Transcription in the Embryonic Heart: Role of the Endoplasmic Reticulum Stress Response Element and GATA-4

The transcriptional activation of GRP78, which controls multiple signaling pathways of the unfolded protein response, has been used extensively as an indicator for the onset of endoplasmic reticulum stress in tissue culture systems. Here we investigate the mechanism of Grp78 induction during mouse embryonic development. Our results reveal that in transgenic mouse models, reporter gene activity driven by the Grp78 promoter is strongly activated during early embryonic heart development but subsides in later stages. This activation is strictly dependent on a 100-base pair region of the Grp78 promoter containing the endoplasmic reticulum stress response elements (ERSEs). Previous studies establish that endoplasmic reticulum stress induces in vivo binding of YY1 and the nuclear form of ATF6 to the ERSE. Since the expression of YY1 as well as ATF6 is ubiquitous in the mouse embryo, activation of the Grp78 promoter in the early embryonic heart may involve a specific mechanism. Here we report that GATA-4, a transcription factor essential for heart development, binds to the Grp78 promoter in vivo and activates the ERSE, which does not contain a consensus GATA binding site. GATA-4 cooperatively activates the Grp78 promoter with YY1, and the DNA binding domain of YY1 is necessary and sufficient for this cooperation. In addition, GATA-4 activation of the Grp78 promoter is enhanced by the nuclear form of ATF6, and this synergy is further potentiated by YY1. These results suggest that during early heart organogenesis, Grp78 can be activated through cooperation between the cell type-specific transcription factors and ERSE-binding factors.