SIN3 Regulates Transcriptional and Longevity Responses to Glycolytic Perturbation in Drosophila melanogaster

Cellular metabolism and gene transcription are closely linked. The conserved transcriptional regulator SIN3 acts as a scaffold for histone deacetylase (HDAC)-containing complexes and is crucial for development, stress resistance, and overall organismal health. SIN3 regulates metabolic gene expression in Drosophila cultured cells, however, an understanding of the extent of its role in coordinating responses to metabolic stress in whole organisms is incomplete. In this study, we explored how SIN3 controls glycolytic gene expression across developmental stages and under genetic and dietary disruption of glycolysis in Drosophila melanogaster. Focusing on four key glycolytic enzymes: phosphofructokinase (Pfk), enolase (Eno), pyruvate kinase (Pyk), and pyruvate dehydrogenase beta (Pdhb), we found that reducing Sin3A levels increases their expression in both larvae and adults, indicating that SIN3 plays a consistent role in balancing metabolic gene transcription. Genetic interaction experiments indicate that Sin3A interacts with Pyk and Eno, regulating transcription in a gene-specific manner. Disrupting glycolysis via genetic or dietary means alters glycolytic gene expression, and SIN3 modulates this response. These findings indicate that SIN3 functions as a metabolic sensor, regulating transcription in response to cellular metabolic stress. Additionally, we demonstrate that reducing Sin3A levels shortens Drosophila lifespan on both low- and high-sucrose diets, emphasizing the importance of SIN3 in longevity. Overall, these results show that SIN3 is a context-dependent regulator of glycolytic gene expression and lifespan in Drosophila, integrating metabolic signals with chromatin-based transcriptional regulation. SummaryTo survive and thrive, organisms must adapt to distinct metabolic inputs. We investigated the response of the conserved transcriptional regulator SIN3 to metabolic stress and its control of glycolytic gene expression in Drosophila melanogaster. By measuring glycolytic gene expression, testing genetic interactions, and assessing lifespan under genetic and dietary perturbations, we found that Sin3A knockdown elevates glycolytic gene expression in a gene-specific manner and decreases longevity. SIN3 also modulates transcriptional responses to disrupted glycolysis and influences lifespan under sucrose stress. These findings identify SIN3 as a context-dependent transcription regulator that links gene expression with organismal metabolic adaptation.