Endoplasmic reticulum stress induction of the Grp78/BiP promoter: activating mechanisms mediated by YY1 and its interactive chromatin modifiers.
The unfolded protein response is an evolutionarily conserved mechanism whereby cells respond to stress conditions that target the endoplasmic reticulum (ER). The transcriptional activation of the promoter of GRP78/BiP, a prosurvival ER chaperone, has been used extensively as an indicator of the onset of the UPR. YY1, a constitutively expressed multifunctional transcription factor, activates the Grp78 promoter only under ER stress conditions. Previously, in vivo footprinting analysis revealed that the YY1 binding site of the ER stress response element of the Grp78 promoter exhibits ER stress-induced changes in occupancy. Toward understanding the underlying mechanisms of these unique phenomena, we performed chromatin immunoprecipitation analyses, revealing that YY1 only occupies the Grp78 promoter upon ER stress and is mediated in part by the nuclear form of ATF6. We show that YY1 is an essential coactivator of ATF6 and uncover their specific interactive domains. Using small interfering RNA against YY1 and insertional mutation of the gene encoding ATF6alpha, we provide direct evidence that YY1 and ATF6 are required for optimal stress induction of Grp78. We also discovered enhancement of the ER-stressed induction of the Grp78 promoter through the interaction of YY1 with the arginine methyltransferase PRMT1 and evidence of its action through methylation of the arginine 3 residue on histone H4. Furthermore, we detected ER stress-induced binding of the histone acetyltransferase p300 to the Grp78 promoter and histone H4 acetylation. A model for the ER stress-mediated transcription factor binding and chromatin modifications at the Grp78 promoter leading to its activation is proposed.
Baumeister
Peter
P
Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, 1441 Eastlake Ave., Room 5308, MC-9176, Los Angeles, CA 90089-9176, USA.
Luo
Shengzhan
S
Skarnes
William C
WC
Sui
Guangchao
G
Seto
Edward
E
Shi
Yang
Y
Lee
Amy S
AS
D000123:Acetyltransferases / Q000378:metabolism*; D051702:Activating Transcription Factor 6; D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors / Q000494:pharmacology; D050981:Erythroid-Specific DNA-Binding Factors; D006360:Heat-Shock Proteins / Q000235:genetics*; D051548:Histone Acetyltransferases; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics*; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D011401:Promoter Regions, Genetic / Q000235:genetics*; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D050986:YY1 Transcription Factor; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D051702:Activating Transcription Factor 6; D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D050981:Erythroid-Specific DNA-Binding Factors; D006360:Heat-Shock Proteins; D051548:Histone Acetyltransferases; D018832:Molecular Chaperones; D011484:Protein-Arginine N-Methyltransferases; D034741:RNA, Small Interfering; D019284:Thapsigargin; D014157:Transcription Factors; D050986:YY1 Transcription Factor; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C497111:ATF6 protein, human; C497112:Atf6 protein, mouse; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C494698:YY1 protein, human; C494699:Yy1 protein, mouse