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

Area of Science:

• Cellular biology
• Molecular genetics
• Biochemistry

Background:

• Cell growth requires coordinated gene expression and biomolecule supply to meet metabolic and translational demands.
• The transcription factor Gcn4/ATF4 is known for its role in amino acid starvation response, but its function during rapid cell proliferation is unclear.

Purpose of the Study:

• To investigate the role of Gcn4/ATF4 in maintaining metabolic supply to sustain translation during a methionine-induced growth program in yeast.
• To decipher the genome-wide direct and indirect roles of Gcn4 in this growth context.

Main Methods:

• Integration of transcriptome and ChIP-Seq analysis in yeast.
• Utilizing a methionine-induced growth model to study Gcn4 activity.

Main Results:

• Gcn4/ATF4 is essential for metabolic precursor biosynthesis, particularly lysine and arginine.
• Gcn4/ATF4 directly activates a subset of metabolic genes and globally represses lysine and arginine-enriched transcripts, including those for the translation machinery.
• This Gcn4-mediated supply of lysine and arginine supports translation machinery synthesis and overall protein synthesis capacity.

Conclusions:

• Gcn4/ATF4 acts as a central regulator, enabling metabolic precursor supply to bolster protein synthesis and drive cell growth.
• The study reveals how Gcn4/ATF4 controls both growth and starvation outcomes through context-specific transcriptional outputs.