MicroRNAs are well known to mediate translational repression and mRNA degradation in the cytoplasm. Various microRNAs have also been detected in membrane-compartmentalized organelles, but the functional significance has remained elusive. Here we report that miR-1, a microRNA specifically induced during myogenesis, efficiently enters the mitochondria where it unexpectedly stimulates, rather than represses, the translation of specific mitochondrial genome-encoded transcripts. We show that this positive effect requires specific miR:mRNA base-pairing and Ago2, but not its functional partner GW182, which is excluded from the mitochondria. We provide evidence for the direct action of Ago2 in mitochondrial translation by CLIP-seq, functional rescue with mitochondria-targeted Ago2, and selective inhibition of the microRNA machinery in the cytoplasm. These findings unveil a positive function of microRNA in mitochondrial translation and suggest a highly coordinated myogenic program via miR-1 mediated translational stimulation in the mitochondria and repression in the cytoplasm.

SummaryMicroRNA biogenesis is known to be modulated by a variety of RNA binding proteins (RBPs), but in most cases, individual RBPs appear to influence the processing of a small subset of target miRNAs. We herein report that the RNA binding NONO/PSF heterodimer binds a large number of expressed pri-miRNAs in HeLa cells to globally enhance pri-miRNA processing by the Drosha/DGCR8 Microprocessor. Because NONO/PSF are key components of paraspeckles organized by the lncRNA NEAT1, we further demonstrate that NEAT1 also has a profound effect on global pri-miRNA processing. Mechanistic dissection reveals that NEAT1 broadly interacts with NONO/PSF as well as many other RBPs, and that multiple RNA segments in NEAT1, including a “pseudo pri-miRNA” near its 3′ end, help attract the Microprocessor. These findings suggest a bird nest model for a large non-coding RNA to orchestrate efficient processing of almost an entire class of small non-coding RNAs in the nucleus.

MicroRNA (miRNA) are well known to target 3’ untranslated regions (3’UTR) in mRNAs to silence gene expression at post-transcriptional levels. Multiple reports have also indicated the capability of miRNAs to target protein-coding sequences (CDS); however, miRNAs have been generally believed to function in a similar mechanism(s) regardless of the location of their action sites. We herein report a class of miRNA recognition elements (MREs) that exclusively function in CDS regions in humans. Through functional and mechanistic characterization of these “unusual” MREs, we demonstrate that CDS-targeted miRNAs require extensive base pairings in the 3’ side rather than the 5’ seed; cause gene silencing in an Argonaute-dependent, but GW182-independent manner; and repress translation by inducing transient ribosome stalling instead of mRNA destabilization. These findings reveal distinct mechanisms and functional consequences for miRNAs to target CDS versus 3’UTR and suggest that CDS-targeted miRNAs may enlist a translational quality control (QC)-related mechanism to regulate translation in mammalian cells.

H epatocellular carcinoma (HCC) is the sixth most common type of cancer and ranks third as a cause of cancer-related death globally. Worldwide, approximately 630 000 new cases of HCC occur annually, with more than half of these cases occurring in China (1). This disease is related to hepatitis B virus (HBV) infection in almost 70%-90% of cases in the highly endemic Asia-Pacific regions, especially in China (2, 3). Partial hepatectomy and liver transplantation are the most effective curative treatments, albeit in a limited number of cases (4). Indeed, the 5-year recurrence rates after surgical treatment and liver transplantation are as high as 70% and 35%, respectively (5-7). It is, therefore, necessary to find effective biomarkers that can identify aggressive behavior and predict tumor recurrence after liver resection and transplantation.In HCC, the presence of microvascular invasion (MVI) is a histopathologic feature indicative of aggressive behavior (8). Previous studies have identified MVI as a major risk factor for early recurrence in the first two years after liver resection and transplantation (9). Precise identification of MVI involvement in patients with HCC is critical to develop treatment strategies and arrive at prognoses. Over the past decade, researchers have made persistent endeavors towards the preoperative prediction of MVI (10-12). Although several radiologic features on contrast-enhanced magnetic resonance imaging (MRI) and computed tomography (CT) images (such as tumor margin, internal arteries, and hypodense halos) are known PURPOSE We aimed to develop and validate a radiomics nomogram for preoperative prediction of microvascular invasion (MVI) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODSA total of 304 eligible patients with HCC were randomly divided into training (n=184) and independent validation (n=120) cohorts. Portal venous and arterial phase computed tomography data of the HCCs were collected to extract radiomic features. Using the least absolute shrinkage and selection operator algorithm, the training set was processed to reduce data dimensions, feature selection, and construction of a radiomics signature. Then, a prediction model including the radiomics signature, radiologic features, and alpha-fetoprotein (AFP) level, as presented in a radiomics nomogram, was developed using multivariable logistic regression analysis. The radiomics nomogram was analyzed based on its discrimination ability, calibration, and clinical usefulness. Internal cohort data were validated using the radiomics nomogram. RESULTSThe radiomics signature was significantly associated with MVI status (P < 0.001, both cohorts). Predictors, including the radiomics signature, nonsmooth tumor margin, hypoattenuating halos, internal arteries, and alpha-fetoprotein level were reserved in the individualized prediction no- CONCLUSIONThe radiomics nomogram, as a noninvasive preoperative prediction method, shows a favorable predictive accuracy for MVI status in patients with HBV-related HCC.

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PIWI interacting RNAs (piRNAs) are highly expressed in germline cells and are involved in maintaining genome integrity by silencing transposons. These are also involved in DNA/histone methylation and gene expression regulation in somatic cells of invertebrates. The functions of piRNAs in somatic cells of vertebrates, however, remain elusive. We found that snoRNA-derived and C (C′)/D′ (D)-box conserved piRNAs are abundant in human CD4 primary T-lymphocytes. piRNA (piR30840) significantly downregulated interleukin-4 (IL-4) via sequence complementarity binding to pre-mRNA intron, which subsequently inhibited the development of Th2 T-lymphocytes. Piwil4 and Ago4 are associated with this piRNA, and this complex further interacts with Trf4-Air2-Mtr4 Polyadenylation (TRAMP) complex, which leads to the decay of targeted pre-mRNA through nuclear exosomes. Taken together, we demonstrate a novel piRNA mechanism in regulating gene expression in highly differentiated somatic cells and a possible novel target for allergy therapeutics.

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