Abstract 2183 Metabolic enzymes in the nucleus: the role of local acetyl-CoA

Cells are capable of adapting their metabolism in response to changes in nutrient availability, and this can cause changes in gene expression. Recent studies have revealed that certain metabolic enzymes, such as acetyl-CoA synthetase Acs2, are present in the nucleus. Acs2 plays a vital role in producing acetyl-CoA from acetate, which is crucial for histone acetylation, an epigenetic mark that activates transcription. However, the importance of local acetyl-CoA production in the nucleus is not fully understood. Our research aims to determine the nuclear role of Acs2 by exploring the consequences of its exclusion from the nucleus in yeast cells. To evaluate the effects of excluding Acs2 from the nucleus, we employed several methods, including growth curve and spotting assays, western blotting, and high throughput sequencing, including RNA- and ChIP-sequencing. We also studied several suppressor mutants that appeared to compensate for the absence of Acs2 in nuclei. Our findings indicate that the exclusion of Acs2 from the nucleus results in a growth defect in yeast cells. Transcriptome analysis reveals that genes from the ergosterol biosynthetic pathway, which require acetyl-CoA, are perturbed in the mutant. Ergosterol is essential for maintaining cell membrane integrity. Additionally, pathways that sense cell wall stress are upregulated in the mutant, and the mutant is more sensitive to drugs that target ergosterol. Interestingly, the overall histone acetylation levels remain unaffected in the mutant. In conclusion, our study demonstrates that excluding Acs2 from the nucleus results in significant changes in the phenotype and gene expression profile of cells, without major changes in histone acetylation levels. Our ongoing efforts are focused on understanding the underlying mechanisms of these observed effects.