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

## TL;DR

This study shows that NF-κB in fruit flies can control metabolism by altering chromatin structure, preventing overactivation of nutrient-dependent processes.

## Contribution

The paper reveals a novel epigenetic role of NF-κB in restraining metabolic gene activation through chromatin modulation.

## Key findings

- NF-κB/Relish restricts chromatin accessibility at metabolic gene loci by modulating histone acetylation.
- HDAC6 interacts with NF-κB/Relish to repress metabolic transcriptional programs.
- NF-κB acts as a repressor, diverging from its typical role as a transcriptional activator.

## Abstract

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 κB (NF-κB), 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-κB (Relish) can restrain nutrient-dependent metabolic transcriptional programs that control cellular catabolism of energy substrates, divergent from the protein’s canonical role as a transcriptional activator. NF-κB/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 interacts with NF-κB/Relish at NF-κB 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.

Graphical Abstract