IMMUDROSO

Aberrant regulation of the inflammatory response is highly suspected in numerous cancers and chronic inflammatory diseases. NF-kB transcription factors are key actors in the transcriptional cascade leading to inflammation, they activate genes with pro- or anti-inflammatory activities. Massive efforts in drug development have been made to interfere with NF-kB signaling during inflammatory diseases. However, switching off the entire NF-kB pathway can lead to numerous adverse effects. In this context, our laboratory has discovered that Akirin, an evolutionarily conserved player in the NF-kB pathway, is required for the transcription of pro-inflammatory genes, but not for the NF-kB-dependent genes contributing to the down-regulation of inflammation. This discovery points to a unique dichotomy between Akirin-dependent and -independent genes activation, allowing for the first time to decouple activation and resolution of inflammation. We could show that the SWI/SNF chromatin-remodeler and a specific histone modification (H3K4ac) operate this dichotomy. Lately, a study (Dann et al, 2017, Nature) showed that differential epigenetic marks are instrumental for the selective recruitment of chromatin remodelers. Collectively, this suggests that during the inflammatory response a particular chromatin-code exists to trigger specific activation of Akirin-dependent genes during inflammation. We proposed here to decipher this code. We will combine ChIP and ATAC-Sequencing, Drosophila genetics to explore and validate at genome-wide level the epigenetic switch occurring at Akirin-dependent NF-kB target genes upon immune challenge. This project would allow a comprehensive view of the inflammatory process and bring new insights about the molecular mechanisms that govern NF-kB transcriptional selectivity. More precisely, we expect that uncovering HMEs and chromatin remodelers involved in Drosophila Akirin-dependent NF-kB transcriptional selectivity will unravel the epigenetic fine-tuning of pro-inflammatory genes expression. In-fine, we strongly believe that this collaborative research project will extend our fundamental knowledge in the understanding of the ancestral molecular mechanisms governing the selective choice of NF-kB target gene expressions in Drosophila. The perfect completion of this research project will pave the way for a future application aimed at exploring NF-kB selectivity in the mammalian system, with a new consortium.