Abstract
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.
Highlights
Blood vessel formation is an essential developmental process required for the survival of all vertebrates and much effort has been devoted to reveal the underlying molecular pathways and to identify key molecules that regulate different aspects of this process
The vascular anatomy and the mechanisms involved in vessel formation are highly conserved among vertebrates
Hematopoietic Stem Cells (HSC) emerge from the ventral wall of the dorsal aorta (DA, Fig 1D and 1D’), before migrating into the Caudal Hematopoietic Tissue (CHT) (Fig 1D) where Hematopoietic Stem and Progenitor Cells (HSPCs) proliferate and undergo maturation [28]
Summary
Blood vessel formation is an essential developmental process required for the survival of all vertebrates and much effort has been devoted to reveal the underlying molecular pathways and to identify key molecules that regulate different aspects of this process. Adhesion molecules have been shown to be crucial players in vascular morphogenesis as Vascular Endothelial cadherin (VE-cad/ Cdh5) and endothelial cell-selective adhesion molecule (Esama) are essential for junction remodeling and blood vessel elongation in zebrafish [8,9]. The chromatin-remodeling enzyme BRG1 affects early vascular development as well as hematopoiesis in mice [13], and the histone acetyltransferase P300 has been proposed to be recruited at the promoter of specific endothelial genes by the ETS transcription factor ERG (ETS Related Gene) to control their expression both in vivo in zebrafish and in HUVECs (Human Umbilical Vein Endothelial Cells) [14,15]
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