MAF converts metabolic state into superenhancer architecture and dependency in myeloma [RPMI8226 p300 ChIP-seq]

Lineage-specific transcription factors govern superenhancer assemblies that impose extreme transcriptional output, but how metabolic capacity sustains these regulatory hubs remains unresolved. By integrating metabolomic, epigenomic and chromatin architecture analyses, we identify a previously unrecognized role for MAF in metabolically driven histone acetylation, including the superenhancer-defining mark H3K27ac, through enhanced acetyl-CoA availability derived from rewired glutamine anaplerosis. The channeling of acetylation donors to high-demand enhancer microdomains is facilitated by nucleus-localizing metabolic enzyme citrate synthase, thereby alleviating metabolically constrained chromatin states. This process is further reinforced by MAF-dependent transcriptional regulation of the rate-limiting acetyltransferase p300, culminating in a globally elevated yet spatially precise hyperacetylated chromatin landscape that drives expression of core myeloma oncogenes. Yet, this metaboloepigenetic coupling comes at the cost of conditional vulnerability, unmasking superenhancers as liabilities that can be selectively destabilized with dietary nutrient restriction, as exemplified by the superenhancer-encoded dependency ZC3H3. Our study thus highlights an underappreciated dimension of superenhancer biology, positioning MAF as a metabolic gatekeeper of enhancer function.