Prmt5 promotes vascular morphogenesis independently of its methyltransferase activity

Author summary Blood vessel formation is an essential developmental process required for the survival of all vertebrates. The vascular anatomy and the mechanisms involved in vessel formation are highly conserved among vertebrates. Hence, we used zebrafish as a model, to decipher the role and the mode of action of Prmt5, an enzyme known to regulate gene expression, in vascular morphogenesis and in blood cell formation in vivo. Using different approaches, we highlighted a key role of Prmt5 during both processes. However, we found that while blood cell formation required Prmt5 enzymatic activity, vascular morphogenesis was independent on its activity. Prmt5 has been proposed as a therapeutic target in many diseases, including cancer. Yet, we show here that Prmt5 acts at least in part independently of its methyltransferase activity to regulate vascular morphogenesis. By shedding light on a mechanism of action of Prmt5 that will be insensitive to enzymatic inhibitors, our data calls forth the design of alternative drugs. In addition, this non-canonical function of Prmt5 may have a more pervasive role than previously thought in physiological conditions, i.e. during development, but also in pathological situations such as in tumor angiogenesis and certainly deserves more attention in the future. During development, the vertebrate vasculature undergoes major growth and remodeling. While the transcriptional cascade underlying blood vessel formation starts to be better characterized, little is known concerning the role and mode of action of epigenetic enzymes during this process. Here, we explored the role of the Protein Arginine Methyl Transferase Prmt5 in blood vessel formation as well as hematopoiesis using zebrafish as a model system. Through the combination of different prmt5 loss-of-function approaches we highlighted a key role of Prmt5 in both processes. Notably, we showed that Prmt5 promotes vascular morphogenesis through the transcriptional control of ETS transcription factors and adhesion proteins in endothelial cells. Interestingly, using a catalytic dead mutant of Prmt5 and a specific drug inhibitor, we found that while Prmt5 methyltransferase activity was required for blood cell formation, it was dispensable for vessel formation. Analyses of chromatin architecture impact on reporter genes expression and chromatin immunoprecipitation experiments led us to propose that Prmt5 regulates transcription by acting as a scaffold protein that facilitates chromatin looping to promote vascular morphogenesis.