Gcn4 mediates SAM allocations and methylation balance between phospholipids and histones

Abstract Balancing SAM allocations for methylation reactions, and maintaining the SAM/SAH ratio is crucial for cellular homeostasis. How cells balance the allocation of methyl pools between different sinks, remains under studied. In this study using S. cerevisiae , we identify a role of the amino acid response regulator Gcn4 (Atf4) in balancing the methyl allocations between phospholipids and histones when methionine is abundant. Here, when SAM/SAH ratio increases during methionine supplementation, Gcn4-dependent outputs critically regulate the appropriate allocation of methyl pools to phospholipids and histones. Gcn4 regulates phospholipid methylation by controlling Ino2 levels, which is a primary transcriptional regulator of phospholipid biogenesis. In the absence of Gcn4, Ino2 levels decrease, leading to the downregulation of the PE methyltransferases Cho2 and Opi3. This downregulation of these methyltransferases reduces SAM consumption for phospholipid biosynthesis, and in turn elevates the SAM/SAH ratio in the cell. The elevated SAM pools are subsequently re-allocated towards histone hyper-methylation. Our study reveals the novel role of Gcn4 as a regulator of phospholipid biosynthesis during methionine sufficiency, highlighting its role in appropriate methyl allocations in cells. This Gcn4-dependent check on methylation is therefore necessary to enable cell proliferation when SAM pools are abundant.