Comprehensive Profiling of Amino Acid Response Uncovers Unique Methionine-Deprived Response Dependent on Intact Creatine Biosynthesis
In order for mammalian cells to live and function, amino acids are required for protein synthesis and the generation of metabolic intermediates. An imbalance or deficiency of amino acids often triggers an “amino acid response” (AAR) to allow cells to adapt to their environment. However, it remains unclear whether the deprivation of any single amino acid leads to similar or different changes compared to the global AAR response or to other single amino acid deficiencies. To answer this question, we removed each or all of the 15 amino acids found in media from cells and comprehensively profiled the resulting changes in their RNA expression. Strikingly, we found a unique and dramatic gene expression program that occurred only when cells were deprived of methionine, but not any other amino acid. We also found that these methionine-specific changes depended on changes in histone modifications and an intact creatine biosynthesis pathway. Methionine deprivation reduced the degree to which histone proteins were indirectly modified by methionine (histone methylation). Creatine biosynthesis consumed methionine’s derivate S-Adenosyl-L-methionine (SAM), contributing to the reduction of histone methylation and an increase in ornithine-mediated signaling. Since methionine restriction may have anti-aging and other medical uses, our findings provide insights that will lead toward a better understanding of the underlying effects of methionine restriction and eventually improve human health.
Vyšlo v časopise:
Comprehensive Profiling of Amino Acid Response Uncovers Unique Methionine-Deprived Response Dependent on Intact Creatine Biosynthesis. PLoS Genet 11(4): e32767. doi:10.1371/journal.pgen.1005158
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1005158
Souhrn
In order for mammalian cells to live and function, amino acids are required for protein synthesis and the generation of metabolic intermediates. An imbalance or deficiency of amino acids often triggers an “amino acid response” (AAR) to allow cells to adapt to their environment. However, it remains unclear whether the deprivation of any single amino acid leads to similar or different changes compared to the global AAR response or to other single amino acid deficiencies. To answer this question, we removed each or all of the 15 amino acids found in media from cells and comprehensively profiled the resulting changes in their RNA expression. Strikingly, we found a unique and dramatic gene expression program that occurred only when cells were deprived of methionine, but not any other amino acid. We also found that these methionine-specific changes depended on changes in histone modifications and an intact creatine biosynthesis pathway. Methionine deprivation reduced the degree to which histone proteins were indirectly modified by methionine (histone methylation). Creatine biosynthesis consumed methionine’s derivate S-Adenosyl-L-methionine (SAM), contributing to the reduction of histone methylation and an increase in ornithine-mediated signaling. Since methionine restriction may have anti-aging and other medical uses, our findings provide insights that will lead toward a better understanding of the underlying effects of methionine restriction and eventually improve human health.
Zdroje
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Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
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