Circular RNA profiling identifiescirc5078as aBMPR2-derived regulator of endothelial translation

Abstract

AbstractGermline loss-of-functionBMPR2mutations are the leading genetic cause of pulmonary arterial hypertension (PAH) and are strongly linked to aberrant endothelial proliferation and impaired translational stress responses. While these effects are generally attributed to a loss of the type-II bone morphogenetic protein receptor (BMPR-II), we used circular RNA profiling to identifycirc5078, aBMPR2-derived circular RNA that regulates endothelial translation and cellular phenotype.circ5078and linearBMPR2mRNA exert opposing effects on endothelial proliferation and stress granule formation, while influencing the translational efficiency of multiple genes by regulating ribosome assembly and translational initiation. In PAH patient-derived endothelial cells lacking linearBMPR2mRNA,circ5078depletion rescued impaired translational stress responses by rebalancing circular to linear transcript levels, independent of BMPR-II protein. By identifyingcirc5078as a functionalBMPR2gene product, this work reveals interdependent roles for both linear and circularBMPR2transcripts as regulators endothelial translation and proliferation.