title: ATF4-dependent regulation of the JMJD3 gene during amino acid deprivation can be rescued in Atf4-deficient cells by inhibition of deacetylation.
abstract: Following amino acid deprivation, the amino acid response (AAR) induces transcription from specific genes through a collection of signaling mechanisms, including the GCN2-eIF2-ATF4 pathway. The present report documents that the histone demethylase JMJD3 is an activating transcription factor 4 (ATF4)-dependent target gene. The JMJD3 gene contains two AAR-induced promoter activities and chromatin immunoprecipitation (ChIP) analysis showed that the AAR leads to enhanced ATF4 recruitment to the C/EBP-ATF response element (CARE) upstream of Promoter-1. AAR-induced histone modifications across the JMJD3 gene locus occur upon ATF4 binding. Jmjd3 transcription is not induced in Atf4-knock-out cells, but the AAR-dependent activation was rescued by inhibition of histone deacetylation with trichostatin A (TSA). The TSA rescue of AAR activation in the absence of Atf4 also occurred for the Atf3 and C/EBP homology protein (Chop) genes, but not for the asparagine synthetase gene. ChIP analysis of the Jmjd3, Atf3, and Chop genes in Atf4 knock-out cells documented that activation of the AAR in the presence of TSA led to specific changes in acetylation of histone H4. The results suggest that a primary function of ATF4 is to recruit histone acetyltransferase activity to a sub-set of AAR target genes. Thus, absolute binding of ATF4 to these particular genes is not required and no ATF4 interaction with the general transcription machinery is necessary. The data are consistent with the hypothesis that ATF4 functions as a pioneer factor to alter chromatin structure and thus, enhance transcription in a gene-specific manner.
authors.affiliation: Department of Biochemistry and Molecular Biology, Genetics Institute, Shands Cancer Center, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Jixiu
authors.initials: J
authors.lastname: Shan
authors.forename: Lingchen
authors.initials: L
authors.lastname: Fu
authors.forename: Mukundh N
authors.initials: MN
authors.lastname: Balasubramanian
authors.forename: Tracy
authors.initials: T
authors.lastname: Anthony
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kilberg
mesh_terms: D000107:Acetylation / Q000187:drug effects; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020218:Response Elements; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: C497109:ATF4 protein, human; C081452:Atf4 protein, mouse; D002843:Chromatin; C497249:DDIT3 protein, human; C497250:Ddit3 protein, mouse; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; C012589:trichostatin A; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; C523761:Kdm6b protein, mouse; D006655:Histone Deacetylases