title: Transcriptional cross talk between orphan nuclear receptor ERRγ and transmembrane transcription factor ATF6α coordinates endoplasmic reticulum stress response.
abstract: Orphan nuclear receptor ERRγ 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 ERRγ gene remains to be elucidated. Here, we report that activating transcription factor 6α (ATF6α), an endoplasmic reticulum (ER)-membrane-bound basic leucine zipper (bZip) transcription factor, directly regulates ERRγ gene expression in response to ER stress. ATF6α binds to ATF6α responsive element in the ERRγ promoter. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) is required for this transactivation. Chromatin immunoprecipitation (ChIP) assay confirmed the binding of both ATF6α and PGC1α on the ERRγ promoter. ChIP assay demonstrated histone H3 and H4 acetylation occurs at the ATF6α and PGC1α binding site. Of interest, ERRγ along with PGC1α induce ATF6α gene transcription upon ER stress. ERRγ binds to an ERRγ responsive element in the ATF6α promoter. ChIP assay confirmed that both ERRγ and PGC1α bind to a site in the ATF6α 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 ERRγ and ATF6α gene transcription.
authors.affiliation: Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Science and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Jagannath
authors.initials: J
authors.lastname: Misra
authors.forename: Don-Kyu
authors.initials: DK
authors.lastname: Kim
authors.forename: Woogyun
authors.initials: W
authors.lastname: Choi
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Back
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
mesh_terms: D051702:Activating Transcription Factor 6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; C490917:ESRRG protein, human; C490916:Esrrg protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011960:Receptors, Estrogen; D014157:Transcription Factors