A complex interplay between SAM synthetase and the epigenetic regulator SIN3 controls metabolism and transcription

The SIN3 histone-modifying complex regulates the expression of multiple methionine catabolic genes, including SAM synthetase (Sam-S), as well as SAM levels. To further dissect the relationship between methionine catabolism and epigenetic regulation by SIN3, we sought to identify genes and metabolic pathways controlled by SIN3 and SAM synthetase (SAM-S) in Drosophila melanogaster Using several approaches, including RNAi-mediated gene silencing, RNA-Seq- and quantitative RT-PCR-based transcriptomics, and ultra-high-performance LC-MS/MS- and GC/MS-based metabolomics, we found that, as a global transcriptional regulator, SIN3 impacted a wide range of genes and pathways. In contrast, SAM-S affected only a narrow range of genes and pathways. The expression and levels of additional genes and metabolites, however, were altered in Sin3A+Sam-S dual knockdown cells. This analysis revealed that SIN3 and SAM-S regulate overlapping pathways, many of which involve one-carbon and central carbon metabolisms. In some cases, the factors acted independently; in some others, redundantly; and for a third set, in opposition. Together, these results, obtained from experiments with the chromatin regulator SIN3 and the metabolic enzyme SAM-S, uncover a complex relationship between metabolism and epigenetic regulation.