UCLA

Through billions of years of evolution, immune cells have developed diverse mechanisms to resolve pathogenic infection and heal injury. Proper immune cell activation includes receptor- ligand engagement, intracellular signaling cascades, and transcriptome-wide changes. Dysregulation of proinflammatory cytokines during infection can lead to severe complications. The NF-kB family regulates many pro-inflammatory cytokines associated with inflammation and immune system imbalance, such as Tnfa, Il1b, and Il6. Although NF-kB is one of the best-studied transcription factors, the molecular mechanisms underlying dimer specific function remain largely unknown. Our research explores the role of dimers that are not essential for cellular or organismal survival but have distinct roles in immune cell activation. This research employs a macrophage model system to define dimer-specific roles of NF-kB and the molecular mechanisms underlying their regulation. Using a reductionist system enables us to explore dimer-specific functions with unprecedented depth in the cell context. We focused on c-Rel and p50 due to their potent activation downstream of viral and bacterial PRRs and their highly specific roles in immune cellactivation. We employ both genomic and biochemical approaches such as RNA-seq, ChIP-seq, Sequential ChIP-seq, EMSAs, and co-immunoprecipitations to uncover the mechanistic role of c- Rel and p50. This research provides novel insights into the regulatory logic employed by NF-kB by revealing the underlying mechanisms that make dimer-specific functions possible.