Prmt5 promotes vascular morphogenesis independently of its methyltransferase activity

Aurélie Quillien; Guerric Gilbert; Manon Boulet; Séverine Ethuin; Lucas Waltzer; Laurence Vandel

doi:10.1371/journal.pgen.1009641

Prmt5 promotes vascular morphogenesis independently of its methyltransferase activity

PLoS Genet. 2021 Jun 21;17(6):e1009641. doi: 10.1371/journal.pgen.1009641. eCollection 2021 Jun.

Authors

Aurélie Quillien^{1

2}, Guerric Gilbert³, Manon Boulet^{1

3}, Séverine Ethuin¹, Lucas Waltzer³, Laurence Vandel^{1

3}

Affiliations

¹ Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France.
² RESTORE, INSERM UMR1301, CNRS UMR5070, Université Paul Sabatier, Université de Toulouse, Toulouse, France.
³ Université Clermont Auvergne, CNRS, INSERM, iGReD, Clermont-Ferrand, France.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Chromatin / chemistry
Chromatin / metabolism
Embryo, Nonmammalian
Endothelial Cells / cytology
Endothelial Cells / metabolism
Gene Expression Regulation, Developmental*
Hematopoiesis / genetics*
Morphogenesis / genetics*
Mutation
Neovascularization, Physiologic / genetics*
Protein Isoforms / genetics
Protein Isoforms / metabolism
Protein-Arginine N-Methyltransferases / genetics*
Protein-Arginine N-Methyltransferases / metabolism
Proto-Oncogene Proteins c-ets / genetics*
Proto-Oncogene Proteins c-ets / metabolism
Signal Transduction
Transcription, Genetic
Zebrafish / genetics*
Zebrafish / growth & development
Zebrafish / metabolism
Zebrafish Proteins / genetics*
Zebrafish Proteins / metabolism

Substances

Chromatin
Protein Isoforms
Proto-Oncogene Proteins c-ets
Zebrafish Proteins
etv1 protein, zebrafish
PRMT5 protein, zebrafish
Protein-Arginine N-Methyltransferases

Grants and funding

This work was supported by the French Muscular Dystrophy Association https://www.afm-telethon.fr (grant 20102) and from the Fondation ARC pour la Recherche Contre le Cancer https://www.fondation-arc.org (grant SFI20121205590) to LV; By the Agence Nationale pour la Recherche (ANR) https://www.anr.fr (grant ANR-17-CE12-0030-03) and the Fondation ARC (grant PJA20171206371) to LW. AQ was the recipient of a post-doctoral fellowship from the Fondation ARC (grant PDF20140601073) and GG got a PhD fellowship from the University Clermont-Auvergne https://www.uca.fr. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.