Long non-coding RNA TYKRIL controls pericyte function and survival in the cardiovascular and central nervous system through regulation of p53 activity and PDGFRß expression. Homo sapiens

Vessel maturation is dependent on platelet derived growth factor (PDGF), which signals via tyrosine kinase receptors and facilitates recruitment of pericytes. Long noncoding RNAs (lncRNAs) regulate endothelial and smooth muscle cell properties, but their role in pericyte function is unclear. Using RNA sequencing, we identify the hypoxia induced lncRNA “Tyrosine kinase receptor inducing lncRNA” (TYKRIL) as a species conserved lncRNA which regulates pericyte function by controlling PDGF receptor beta (PDGFRß) expression in vitro, in vivo and in human disease. TYKRIL preferentially binds to the N-terminus of p53, thereby acting as a p53 decoy molecule that prevents the interaction with its co-activator p300, which augments the expression of the known p53 target PDGFRß. In summary, our results identify TYKRIL as a key regulator of pericyte function by acting as a previously unknown modulator of p53 activity which may enable to develop novel therapeutic concepts in PDGFRß and p53 dependent disease states. Overall design: To identify the hypoxia regulated transcriptome in human pericytes, cells were exposed towards 24 hours of hypoxia (1%O2, 5% CO2, humidified atmosphere). Normoxic controls were kept at 20% O2, 5% CO2, humidified atmosphere. Hypoxia was performed in 3 independent experiments. Total, ribosomal depleted RNA was analyzed by RNA deep sequencing following hypoxia. To investigate the impact of the long noncoding RNA TYKRIL on the pericyte transcriptome, TYKRIL was silenced by LNA GapmeRs, controls were treated with scramble LNA GapmeR control. TYKRIL was silenced in 3 independent experiments and total, ribosomal depleted RNA was subsequently analyzed via RNA deep sequencing.