Network architecture of transcriptomic stress responses in zebrafish embryos

Protein-protein interaction (PPI) network topology can contribute to explain fundamental 13 properties of genes, from expression levels to evolutionary constraints. Genes central to a network 14 are more likely to be both conserved and highly expressed, whereas genes that are able to evolve 15 in response to selective pressures but expressed at lower levels are located on the periphery of the 16 network. The stress response is likewise thought to be conserved, however, experimental evidence 17 for these patterns is limited. We examined whether the transcriptomic response to two 18 environmental stressors (heat, UV, and their combination) is related to PPI architecture in zebrafish 19 (Danio rerio) embryos. We show that stress response genes are situated more centrally in the PPI 20 network. The transcriptomic response to heat was located in both central and peripheral positions, 21 whereas UV response occupied central to intermediate positions. Across treatments, differentially 22 expressed genes in different parts of the network affected identical phenotypes. Our results indicate 23 that the zebrafish stress response has mostly conserved but also some stressor-specific aspects. 24 These properties can aid in better understanding the organismal response to diverse and co-25 occurring stressors. Network position was further linked to the magnitude of fold changes of genes 26 and types and number of linked phenotype components. Given the speed of contemporary changes 27 in aquatic ecosystems, our approach can aid in identifying novel key regulators of the systemic 28 response to specific stressors. 29 30