Insights into the early evolution of NF-kappaB signaling based on computational analyses of cnidarian genomes and transcriptomes
Lubinski, Tristan James
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NF-kappaB is an ancient transcription factor that is known to play a central role in regulating cellular stress responses in vertebrates and insects, including the innate immune response, and the response to a range of physiochemical insults such as UV radiation and oxidative stress. The early evolution of this pathway is not well understood, because little is known about NF-kappaB signaling in so-called basal animal lineages (e.g., sponges, cnidarians) or closely related outgroups to the Metazoa. Key to understanding the function of a transcription factor is to identify the target genes whose transcription it regulates. To investigate the regulatory role of NF-kappaB in basal animals, specifically the sea anemone Nematostella vectensis, I developed ForSite, a computational tool that identifies putative transcription factor binding sites in the genome in proximity to expressed genes, and I helped to generate a new annotated reference transcriptome for N. vectensis. After demonstrating that ForSite could be used to identify a set of genes enriched for known NF-kappaB targets in human, I applied ForSite along with multiple winnowing criteria (co-localization of p300 binding; evolutionary conservation of target genes) to identify a high-priority list of potential NF-kappaB targets in the anemone. Among the most convincing set of likely target genes are members of a conserved anti-viral pathway, which suggests NF-kappaB plays an ancient role in innate immunity that dates to the cnidarian-bilaterian ancestor. Application of ForSite to two additional cnidarian species, Hydra magnipapillata and Acropora digitifera, failed to show significant conservation of regulation of biological processes by NF-kappaB among the cnidarian species.