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

Author summary Cell growth needs a ready supply of chemical building blocks (resources), which requires careful management. These resources provide energy, and help synthesize proteins through the process of translation. Some metabolites, such as methionine, push cells to grow even if resources are limited. How cells manage or obtain resources in these conditions is not well known. However, cells must activate 'master regulators', such as some transcription factors, to orchestrate programs to manufacture these building blocks. Here, using yeast cells as a model, we show how one such master regulator, the Gcn4/ATF4 transcription factor, can drive a growth program when activated by methionine. Although Gcn4 is well studied for its role in managing starvation, we find that it can perform similar functions when triggered by methionine, but in this case push cells to grow rapidly. It helps cells to produce a steady supply of amino acids (which are important building blocks), and simultaneously 'manage' the high rates of protein translation that are required in order to grow rapidly. This study highlights basic concepts of how cell growth is managed, and may be important for understanding similar observations from several cancers. Growth and starvation are considered opposite ends of a spectrum. To sustain growth, cells use coordinated gene expression programs and manage biomolecule supply in order to match the demands of metabolism and translation. Global growth programs complement increased ribosomal biogenesis with sufficient carbon metabolism, amino acid and nucleotide biosynthesis. How these resources are collectively managed is a fundamental question. The role of the Gcn4/ATF4 transcription factor has been best studied in contexts where cells encounter amino acid starvation. However, high Gcn4 activity has been observed in contexts of rapid cell proliferation, and the roles of Gcn4 in such growth contexts are unclear. Here, using a methionine-induced growth program in yeast, we show that Gcn4/ATF4 is the fulcrum that maintains metabolic supply in order to sustain translation outputs. By integrating 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 lysine and arginine enriched transcripts, which include genes encoding the translation machinery. The Gcn4 dependent lysine and arginine supply thereby maintains the synthesis of the translation machinery. This is required to maintain translation capacity. Gcn4 consequently enables metabolic-precursor supply to bolster protein synthesis, and drive a growth program. Thus, we illustrate how growth and starvation outcomes are both controlled using the same Gcn4 transcriptional outputs that function in distinct contexts.