Circular RNA profiling identifies circ5078 as a BMPR2-derived regulator of endothelial translation

Germline loss-of-function BMPR2 mutations 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 identify circ5078, a BMPR2-derived circular RNA that regulates endothelial translation and cellular phenotype. circ5078 and linear BMPR2 mRNA 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 linear BMPR2 mRNA, circ5078 depletion rescued impaired translational stress responses by rebalancing circular to linear transcript levels, independent of BMPR-II protein. By identifying circ5078 as a functional BMPR2 gene product, this work reveals interdependent roles for both linear and circular BMPR2 transcripts as regulators endothelial translation and proliferation To investigate the role of BMPR2 derived RNAs on endothelial translation, primary pulmonary artery endothelial cells were treated with siControl, siLinear, si5078 or siLinear+5078. Lysates from these cells were separated on 10-45% sucrose gradients, and equal volumes of RNA from fractions 8-13 were pooled and sequenced, alongside samples representing the total input to sucrose gradients.