Transcriptional cross talk between orphan nuclear receptor ERRγ and transmembrane transcription factor ATF6α coordinates endoplasmic reticulum stress response

Orphan nuclear receptor ERR gamma is a member of nuclear receptor superfamily that regulates several important cellular processes including hepatic glucose and alcohol metabolism. However, mechanistic understanding of transcriptional regulation of the ERR gamma gene remains to be elucidated. Here, we report that activating transcription factor 6 alpha (ATF6 alpha), an endoplasmic reticulum (ER)-membrane-bound basic leucine zipper (bZip) transcription factor, directly regulates ERR gamma gene expression in response to ER stress. ATF6 alpha binds to ATF6 alpha responsive element in the ERR gamma promoter. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) is required for this transactivation. Chromatin immunoprecipitation (ChIP) assay confirmed the binding of both ATF6 alpha and PGC1 alpha on the ERR gamma promoter. ChIP assay demonstrated histone H3 and H4 acetylation occurs at the ATF6 alpha and PGC1 alpha binding site. Of interest, ERR gamma along with PGC1 alpha induce ATF6 alpha gene transcription upon ER stress. ERR gamma binds to an ERR gamma responsive element in the ATF6 alpha promoter. ChIP assay confirmed that both ERR gamma and PGC1 alpha bind to a site in the ATF6 alpha promoter that exhibits histone H3 and H4 acetylation. Overall, for the first time our data show a novel pathway of cross talk between nuclear receptors and ER-membrane-bound transcription factors and suggest a positive feed-forward loop regulates ERR gamma and ATF6 alpha gene transcription.