NF-κB restrains nutrient-dependent transcription programs through chromatin modulation in Drosophila

The co-evolution of immune and metabolic systems has endowed immune signaling pathways with distinct control of cellular metabolism. Innate immune transcription factors, such as nuclear factor {kappa}B (NF-{kappa}B), have thus emerged as key regulators of adaptive metabolic responses to changes in diet and nutrition. Utilizing chromatin accessibility genomics, we found that Drosophila NF-{kappa}B (Relish) can restrain nutrient-dependent metabolic transcriptional programs that control cellular catabolism of energy substrates, divergent from the proteins canonical role as a transcriptional activator. NF-{kappa}B/Relish restricts chromatin accessibility through modulating histone acetylation at metabolic target gene loci, which restrains metabolic gene transcription and blocks excessive activation of nutrient-dependent metabolic programs. Targeted genetic screening revealed that histone deacetylase 6 (HDAC6) interacts with NF-{kappa}B/Relish at NF-{kappa}B DNA regulatory motifs to limit chromatin accessibility and repress metabolic transcriptional programs. These results highlight that innate immune transcription factors can epigenetically restrain cellular catabolism to fine-tune nutrient-dependent metabolic adaptation.