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One-Carbon Cycle and Methylation Potential Regulat Behavioral Alcohol Responses via Glutamatergic Neurons

ABSTRACT: Despite the enormous harms of alcohol use disorder (AUD), many mechanisms, as well as effective prevention or treatment strategies, remain elusive. Genetic factors dictate much of AUD risk, which can manifest as increased naïve resistance to alcohol’s intoxicating effects or increased functional tolerance, i.e., brain-mediated increases in resistance upon repeat exposure. The underlying neurobiology of how AUD-associated genes alter these endophenotypes remains poorly understood. Genes implicated in AUDs include ones encoding epigenetic modifiers, such as histone demethylase Kdm3. We previously showed that whole-body and neuronal loss of Kdm3 affect ethanol resistance and tolerance in Drosophila. Here, we investigate the mechanisms of these effects. RNA-seq and pathway analysis on Kdm3KO flies revealed disproportionate upregulation of genes involved in amino acid metabolism, including the 1-carbon pathway. We show that acute amino acid feeding modulates behavioral alcohol responses in a Kdm3-dependent manner. Global manipulation of 1-carbon genes also alters alcohol responses. These phenotypic changes are likely mediated by glycine levels (a substrate of these enzymes) rather than by 1-carbon input. Conversely, neuron-specific manipulations of the methionine cycle change alcohol responses in a pattern that suggests a mechanism via S-adenosyl methionine (SAM), a 1-carbon metabolite that is the universal methyl donor required for epigenetic methylation. Increasing SAM production specifically in glutamatergic neurons decreases alcohol resistance and increases tolerance. Together, these findings reveal distinct mechanisms affecting alcohol responses globally (via glycine) versus neuronally (via SAM), thus revealing a complex but important role of neuronal 1-carbon metabolism in mediating behavior.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE331104 | GEO | 2026/05/19

REPOSITORIES: GEO

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Project description:Besides being building blocks for protein synthesis, amino acids serve a wide variety of cellular functions, including acting as metabolic intermediates for ATP generation and for redox homeostasis. Upon amino acid deprivation, free uncharged tRNAs trigger GCN2-ATF4 to mediate the well-characterized transcriptional amino acid response (AAR). However, it is not clear whether the deprivation of different individual amino acids triggers identical or distinct AARs. Here, we characterized the global transcriptional response upon deprivation of one amino acid at a time. With the exception of glycine, which was not required for the proliferation of MCF7 cells, we found that the deprivation of most amino acids triggered a shared transcriptional response that included the activation of ATF4, p53 and TXNIP. However, there was also significant heterogeneity among different individual AARs. The most dramatic transcriptional response was triggered by methionine deprivation, which activated an extensive and unique response in different cell types. We uncovered that the specific methionine-deprived transcriptional response required creatine biosynthesis. This dependency on creatine biosynthesis was caused by the consumption of S-Adenosyl-L-methionine (SAM) during creatine biosynthesis that helps to deplete SAM under methionine deprivation and reduces histone methylations. As such, the simultaneous deprivation of methionine and sources of creatine biosynthesis (either arginine or glycine) abolished the reduction of histone methylation and the methionine-specific transcriptional response. Arginine-derived ornithine was also required for the complete induction of the methionine-deprived specific gene response. Collectively, our data identify a previously unknown set of heterogeneous amino acid responses and reveal a distinct methionine-deprived transcriptional response that results from the crosstalk of arginine, glycine and methionine metabolism via arginine/glycine-dependent creatine biosynthesis. RNA was extracted by RNAeasy kits (Qiagen) from the MCF7 or PC3 cells which exposed to the control full DMEM or deprived one (or all) amino acid media for 24 or 48 hours.

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One-Carbon Cycle and Methylation Potential Regulat Behavioral Alcohol Responses via Glutamatergic Neurons

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