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

Area of Science:

• Immunology
• Metabolic Regulation
• Epigenetics

Background:

• Immune and metabolic systems co-evolve, with immune signaling pathways controlling cellular metabolism.
• Innate immune transcription factors, such as nuclear factor κB (NF-κB), are key regulators of metabolic adaptation to diet and nutrition.

Purpose of the Study:

• To investigate the role of Drosophila NF-κB (Relish) in regulating nutrient-dependent metabolic transcriptional programs.
• To elucidate the epigenetic mechanisms by which NF-κB controls cellular metabolism.

Main Methods:

• Chromatin accessibility genomics to identify NF-κB target genes.
• Histone acetylation analysis at metabolic gene loci.
• Targeted genetic screening to identify interacting proteins, including histone deacetylase 6.

Main Results:

• Drosophila NF-κB (Relish) restrains nutrient-dependent metabolic transcriptional programs, a role distinct from its canonical activator function.
• NF-κB/Relish restricts chromatin accessibility via histone acetylation, limiting metabolic gene transcription.
• Histone deacetylase 6 interacts with NF-κB/Relish to repress metabolic programs by limiting chromatin accessibility.

Conclusions:

• Innate immune transcription factors can epigenetically restrain cellular catabolism.
• NF-κB plays a novel role in fine-tuning nutrient-dependent metabolic adaptation through epigenetic repression.
• This study uncovers a new layer of regulation at the intersection of immunity and metabolism.