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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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE84730 | GEO | 2017/08/10

SECONDARY ACCESSION(S): PRJNA330964

REPOSITORIES: GEO

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Project description:The blood-brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS). The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes, but the relative contribution of these different components to the BBB remains largely unknown. Here we demonstrate a direct role of pericytes at the BBB in vivo. Using a set of adult viable pericyte-deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular-mass and high-molecular-mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, we show that pericytes function at the BBB in at least two ways: by regulating BBB-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB. The brain microvascular fragments were isolated from mice with different genotypes, each represented by 3-4 biological replicates. Genotypes 1-2: Platelet derived growth factor-B (PDGF-B) retention-motif knockout (pdgfbret/ret) represent the pericyte-deficient situation, and the heterozygous mice (pdgfbret/+) are used as controls. Genotypes 3-4: Hypomorphic PDGF-B mutants that rescue pdgfb-/- null mice, in which a one copy of a conditionally silent human PDGF-B transgene targeted to the Rosa 26 locus (R26P) is turned on by endothelial-specific expression of Cre recombinase. In this data set these mice are named as Tie2Cre, R26P+/0, pdgfb-/- (representing the pericyte-deficient situation). Mice wt for pdgfb (pdgfb+/+) and carrying one silent copy of R26P (R26P+/0), are used as controls. Genotype 5: Adult Notch3+/+ wildtype (WT).

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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

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