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.