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bioRxiv · 10.1101/2025.07.01.662382

Gcn4 mediates SAM allocations and methylation balance between phospholipids and histones

Prasad, S. S.·Vengayil, V.·Laxman, S.·Srinivasan, R.
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Abstract

Methionine availability alters the methylation status of various cellular molecules, and thereby controls metabolic state, via its metabolite S-adenosyl methionine (SAM). In yeast cells, supplementing excess methionine drives cell growth and proliferation, as well as phospholipid biogenesis. High methionine stabilizes the transcription factor Gcn4 (Atf4), which drives an anabolic transcription program to sustain high growth. Here, we investigated whether Gcn4 regulates the allocation of SAM towards distinct methylation outputs, during this methionine-dependent anabolic program. We find that methionine induced Gcn4 increases the expression of phospholipid methyltransferases during methionine supplementation. In{Delta} gcn4 cells, the expression of these methyltransferases significantly decreases, and results in reduced SAM allocations towards phospholipid methylation, alongside increased intracellular SAM, disrupting the balance in the SAM/SAH ratio in these cells. Excess SAM pools are re-allocated to histones, resulting in their hyper-methylation. Collectively, we uncover that Gcn4 modulates SAM allocations towards phospholipid methyltransferases, and the overall methyl allocation between phospholipids and histones. Our study reveals a novel role for Gcn4 in SAM dependent phospholipid biosynthesis in cells growing in methionine sufficiency.

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Prasad, S. S., Vengayil, V., Laxman, S., Srinivasan, R.. 2025-07-03. Gcn4 mediates SAM allocations and methylation balance between phospholipids and histones. https://doi.org/10.1101/2025.07.01.662382

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