GSE75150
Whole genome expression data from WT, Atf4-/-, and Cebpg-/- MEFs under normal and amino acid deprived (AAD) growth conditions
The integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances and ER stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here we show that C/EBP?:ATF4 heterodimers, but not C/EBPß:ATF4 dimers, are the predominant CARE binding species in stressed cells. C/EBP? and ATF4 associate with genomic CAREs in a mutually-dependent manner and co-regulate many ISR genes. By contrast, the C/EBP family members C/EBPß and CHOP were largely dispensable for induction of stress genes.  Cebpg-/- MEFs proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpg-/- mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBP?-deficient newborns die from atelectasis and respiratory failure which can be mitigated by in utero exposure to the anti-oxidant, N-acetyl-cysteine. Cebpg-/- mice on a mixed strain background show improved viability but, upon aging, develop significantly fewer malignant solid tumors compared to WT animals. Our findings identify C/EBP? as a novel anti-oxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells. Overall design: WT, Atf4-/-, and Cebpg-/- MEFs (passage 3) were cultured under normal and AAD conditions.  RNA from each treatment condition was collected in triplicate for hybrization on Affymetrix Mouse Genome 430 2.0 microarrays.