Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK post, Bangalore, India.
National Centre for Biological Sciences-TIFR, GKVK post, Bellary Road, Bangalore, India.
PLoS Genet. 2020 Dec 30;16(12):e1009252. doi: 10.1371/journal.pgen.1009252. eCollection 2020 Dec.
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.
生长和饥饿被认为是两个极端。为了维持生长，细胞使用协调的基因表达程序，并管理生物分子供应，以满足代谢和翻译的需求。全局生长程序通过增加核糖体生物发生和足够的碳代谢、氨基酸和核苷酸生物合成来补充。这些资源是如何被集体管理的是一个基本问题。Gcn4/ATF4 转录因子的作用在细胞面临氨基酸饥饿的情况下得到了最好的研究。然而，在快速细胞增殖的情况下观察到高 Gcn4 活性，并且 Gcn4 在这种生长情况下的作用尚不清楚。在这里，我们使用酵母中的蛋氨酸诱导生长程序表明，Gcn4/ATF4 是维持代谢供应以维持翻译输出的支点。通过整合匹配的转录组和 ChIP-Seq 分析，我们解码了 Gcn4 在这个生长程序中的全基因组直接和间接作用。使代谢前体生物合成不可或缺的基因需要 Gcn4；相比之下，核糖体基因部分受到 Gcn4 的抑制。Gcn4 直接结合启动子区域并转录一组代谢基因，特别是驱动赖氨酸和精氨酸生物合成。Gcn4 还全局抑制赖氨酸和精氨酸富集的转录本，其中包括编码翻译机制的基因。Gcn4 依赖的赖氨酸和精氨酸供应从而维持翻译机制的合成。这是维持翻译能力所必需的。Gcn4 因此能够使代谢前体供应增强蛋白质合成，并推动生长程序。因此，我们说明了如何使用在不同情况下发挥作用的相同 Gcn4 转录输出来控制生长和饥饿的结果。
