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NOVA2 regulates neural circRNA biogenesis.

ABSTRACT: Circular RNAs (circRNAs) are highly expressed in the brain and their expression increases during neuronal differentiation. The factors regulating circRNAs in the developing mouse brain are unknown. NOVA1 and NOVA2 are neural-enriched RNA-binding proteins with well-characterized roles in alternative splicing. Profiling of circRNAs from RNA-seq data revealed that global circRNA levels were reduced in embryonic cortex of Nova2 but not Nova1 knockout mice. Analysis of isolated inhibitory and excitatory cortical neurons lacking NOVA2 revealed an even more dramatic reduction of circRNAs and establishes a widespread role for NOVA2 in enhancing circRNA biogenesis. To investigate the cis-elements controlling NOVA2-regulation of circRNA biogenesis, we generated a backsplicing reporter based on the Efnb2 gene. We found that NOVA2-mediated backsplicing of circEfnb2 was impaired when YCAY clusters located in flanking introns were mutagenized. CLIP (cross-linking and immunoprecipitation) and additional reporter analyses demonstrated the importance of NOVA2 binding sites located in both flanking introns of circRNA loci. NOVA2 is the first RNA-binding protein identified to globally promote circRNA biogenesis in the developing brain.

SUBMITTER: Knupp D

PROVIDER: S-EPMC8266653 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHypoxia has been shown to induce the malignant progression of cancer, including non-small cell lung cancer (NSCLC). Circular RNA (circRNA) is considered to be an important regulator of cancer progression. However, the role of a newly discovered circRNA, circ_0000376, in the progression of NSCLC is unclear.MethodsThe relative expression levels of circ_0000376, miR-1182 and neuro-oncological ventral antigen 2 (NOVA2) were detected via quantitative real-time polymerase chain reaction (qRT-PCR). Glucose consumption and lactate production were determined using Glucose Assay Kit and Lactate Assay Kit, respectively. Moreover, the protein levels of glycolysis markers and NOVA2 were measured using Western blot (WB) analysis. Furthermore, 3-(4, 5-dimethyl-2 thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay was performed to assess cell viability, and transwell assay was employed to evaluate cell migration and invasion. The interaction between miR-1182 and circ_0000376 or NOVA2 was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. In addition, animal experiments were conducted to assess the influence of circ_0000376 silencing on NSCLC tumor growth in vivo.ResultsCirc_0000376 was upregulated in NSCLC, and its high expression was related to the poor overall survival of NSCLC patients. Hypoxia could enhance circ_0000376 expression and promote the glycolysis, viability, migration, and invasion of NSCLC cells. However, silencing of circ_0000376 could inhibit the glycolysis, viability, migration, and invasion of hypoxia-induced NSCLC cells. Additionally, circ_0000376 could sponge miR-1182, and miR-1182 could target NOVA2. MiR-1182 silencing could reverse the inhibitory effect of circ_0000376 knockdown on NSCLC progression, and NOVA2 overexpression also could reverse the suppressive effect of miR-1182 overexpression on NSCLC progression. Meanwhile, miR-1182 inhibitor could invert the negative regulation effect of circ_0000376 silencing on NOVA2 expression. In addition, circ_0000376 knockdown inhibited the NSCLC tumor growth via regulating the miR-1182 and NOVA2 expression in vivo.ConclusionCirc_0000376 promoted NSCLC progression by regulating the miR-1182/NOVA2 axis, suggesting that circ_0000376 might be a potential biomarker for NSCLC treatment.

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NOVA2 regulates neural circRNA biogenesis.

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