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A Primate lncRNA Mediates Notch Signaling During Neuronal Development by Sequestering miRNA [SHSY5Y cells]

ABSTRACT: Long non-coding RNAs (lncRNAs) are a diverse category of transcripts with poor conservation and have expanded greatly in primates, particularly in their brain. We identified a lncRNA, which has acquired 16 microRNA response elements (MREs) for miR-143-3p in the Catarrhini branch of primates. This lncRNA termed LncND (neuro-development) gets expressed in neural progenitor cells and then declines in mature neurons. Binding and release of miR-143-3p, by LncND, can control the expression of Notch. Its expression is highest in radial glia cells in the ventricular and outer subventricular zones of human fetal brain. Down-regulation of LncND in neuroblastoma cells reduced cell proliferation and induced neuronal differentiation, an effect phenocopied by miR-143-3p over-expression and supported by RNA-seq analysis. These findings support a role for LncND in miRNA-mediated regulation of Notch signaling in the expansion of the neural progenitor pool of primates and hence contributing to the rapid growth of the cerebral cortex.

ORGANISM(S): Homo sapiens

PROVIDER: GSE73982 | GEO | 2016/06/23

SECONDARY ACCESSION(S): PRJNA298642

REPOSITORIES: GEO

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Project description:Rationale: Currently, there are no blood-based biomarkers with clinical utility for acute ischemic stroke (IS). microRNAs (miRNAs) show promise as disease markers due to their cell-type specific expression patterns and stability in peripheral blood. Objective: To identify circulating miRNAs associated with acute IS, determine their temporal course up to 90 days post-stroke, and explore their utility as an early diagnostic marker. Methods and Results: We used RNA sequencing to study expression changes of circulating miRNAs in a discovery sample of 20 IS patients and 20 matched healthy control subjects (HCs). We further applied qRT-PCR in independent samples for validation (40 IS patients and 40 matched controls), replication (200 IS patients, 100 HCs), and in 72 patients with transient ischemic attacks (TIA). Sampling of patient plasma was done immediately upon hospital arrival. We identified, validated, and replicated three differentially expressed miRNAs, which were upregulated in IS patients compared to both HCs (miR-125a-5p [1.8-fold; P=1.5x10-6], miR-125b-5p [2.5-fold; P=5.6x10-6], and miR-143-3p [4.8-fold; P=7.8x10-9]) and TIA patients (miR-125a-5p: P=0.003, miR-125b-5p: P=0.003, miR-143-3p: P=0.005). Longitudinal analysis of expression levels up to 90 days after stroke revealed a normalization to control levels for miR-125b-5p and miR-143-3p starting at day two, while miR-125a-5p remained elevated. Levels of all three miRNAs depended on platelet numbers in a platelet spike-in experiment, but were unaffected by chemical hypoxia in N2a cells and in experimental stroke models. In a random forest classification, miR-125a-5p, miR-125b-5p and miR-143-3p differentiated between HCs and IS patients with an area under the curve (AUC) of 0.90 (sensitivity: 85.6%; specificity: 76.3%), which was superior to multimodal cranial computed tomography obtained for routine diagnostics (sensitivity: 72.5%) and previously reported biomarkers of acute IS (neuron specific enolase: AUC=0.69, interleukin 6: AUC=0.82). Conclusions: A set of circulating miRNAs (miR-125a-5p, miR-125b-5p, miR-143-3p) associates with acute IS and might have clinical utility as an early diagnostic marker.

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A Primate lncRNA Mediates Notch Signaling During Neuronal Development by Sequestering miRNA [SHSY5Y cells]

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