Genome-scale reconstruction of Gcn4/ATF4 networks driving a growth program

Growth and starvation are considered opposite ends of a spectrum. To sustain growth, cells must manage biomolecule supply to balance constructive metabolism with high translation, through coordinated gene expression programs. Global growth programs couple increased ribosomal biogenesis with sufficient carbon metabolism, amino acid and nucleotide biosynthesis, and how this is collectively managed is a fundamental question. Conventionally, the role of the Gcn4/ATF4 transcription factor has been studied only in the context of amino acid starvation. However, high Gcn4/ATF4 has been observed in contexts of rapid cell proliferation, and the specific role of Gcn4 in growth contexts are unclear. Here, using a methionine-induced growth program in yeast, we show that Gcn4/ATF4 is the fulcrum through which metabolic supply dependent sustenance of translation outputs is maintained. Integrating time-matched transcriptome and ChIP-Seq analysis, we decipher genome-wide direct and indirect roles for Gcn4 in this growth program. Genes that enable metabolic precursor biosynthesis indispensably require Gcn4; contrastingly ribosomal genes are partly repressed by Gcn4. Gcn4 directly binds promoter-regions and transcribes a subset of metabolic genes, particularly driving lysine and arginine biosynthesis. Gcn4 also globally represses lys/arg enriched transcripts, which include the translation machinery. The sustained Gcn4 dependent lys/arg supply is required to maintain sufficient translation capacity, by allowing the synthesis of the translation machinery itself. Gcn4 thereby enables metabolic-precursor supply to bolster protein synthesis, and drive a growth program. Thus, we illustrate how growth and starvation outcomes are both controled using the same Gcn4 transcriptional outputs, in entirely distinct contexts.