Circular RNAs (circRNAs) are covalently closed, endogenous biomolecules in eukaryotes with tissue-specific and cell-specific expression patterns, whose biogenesis is regulated by specific cis-acting elements and trans-acting factors. Some circRNAs are abundant and evolutionarily conserved, and many circRNAs exert important biological functions by acting as microRNA or protein inhibitors ('sponges'), by regulating protein function or by being translated themselves. Furthermore, circRNAs have been implicated in diseases such as diabetes mellitus, neurological disorders, cardiovascular diseases and cancer. Although the circular nature of these transcripts makes their detection, quantification and functional characterization challenging, recent advances in high-throughput RNA sequencing and circRNA-specific computational tools have driven the development of state-of-the-art approaches for their identification, and novel approaches to functional characterization are emerging.

The biogenesis, biology and characterization of circular RNAs.

Majority of RNAs expressed in animal cells lack protein-coding ability. Unlike other cellular RNAs, circular (circ)RNAs include a large family of noncoding (nc)RNAs that lack the 5′ or 3′ ends. The improvements in high-throughput RNA sequencing and novel bioinformatics tools have led to the identification of thousands of circRNAs in various organisms. CircRNAs can regulate gene expression by influencing the transcription, the mRNA turnover, and translation by sponging RNA-binding proteins and microRNAs. Given the broad impact of circRNA on miRNA activity, there is huge interest in understanding the impact of miRNA sponging by circRNA on gene regulation. In this review, we summarize our current knowledge of the miRNA-circRNA interaction and mechanisms that influence gene expression.

Circular RNAs Act as miRNA Sponges.

Circular RNAs (circRNAs) are a new class of non-coding RNAs formed by covalently closed loops through backsplicing. Recent methodologies have enabled in-depth characterization of circRNAs for identification and potential functions. CircRNAs play important roles in various biological functions as microRNA sponges, transcriptional regulators and combining with RNA binding proteins. Recent studies indicated that some cytoplasmic circRNAs can be effectively translated into detectable peptides, which enlightened us on the importance of circRNAs in cellular physiology function. Internal Ribosome Entry site (IRES)- and N6-methyladenosines (m6A)-mediated cap-independent translation initiation have been suggested to be potential mechanism for circRNA translation. To date, several translated circRNAs have been uncovered to play pivotal roles in human cancers. In this review, we introduced the properties and functions of circRNAs, and characterized the possible mechanism of translation initiation and complexity of the translation ability of circRNAs. We summarized the emerging functions of circRNA-encoded proteins in human cancer. The works on circRNA translation will open a hidden human proteome, and enhance us to understand the importance of circRNAs in human cancer, which has been poorly explored so far.

/pdf/translation-and-functional-roles-of-circular-rnas-in-human-3lqhstie4b.pdf

Translation and functional roles of circular RNAs in human cancer.

MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

Circular RNAs (circRNAs) are a class of single-stranded, covalently closed RNA molecules with a variety of biological functions. Studies have shown that circRNAs are involved in a variety of biological processes and play an important role in the development of various complex diseases, so the identification of circRNA-disease associations would contribute to the diagnosis and treatment of diseases. In this review, we summarize the discovery, classifications and functions of circRNAs and introduce four important diseases associated with circRNAs. Then, we list some significant and publicly accessible databases containing comprehensive annotation resources of circRNAs and experimentally validated circRNA-disease associations. Next, we introduce some state-of-the-art computational models for predicting novel circRNA-disease associations and divide them into two categories, namely network algorithm-based and machine learning-based models. Subsequently, several evaluation methods of prediction performance of these computational models are summarized. Finally, we analyze the advantages and disadvantages of different types of computational models and provide some suggestions to promote the development of circRNA-disease association identification from the perspective of the construction of new computational models and the accumulation of circRNA-related data.

MicroRNAs and complex diseases: from experimental results to computational models.

Circular RNA (circRNA) is a group of RNA family generated by RNA circularization, which was discovered ubiquitously across different species and tissues. However, there is no global view of tissue specificity for circRNAs to date. Here we performed the comprehensive analysis to characterize the features of human and mouse tissue-specific (TS) circRNAs. We identified in total 302 853 TS circRNAs in the human and mouse genome, and showed that the brain has the highest abundance of TS circRNAs. We further confirmed the existence of circRNAs by reverse transcription polymerase chain reaction (RT-PCR). We also characterized the genomic location and conservation of these TS circRNAs and showed that the majority of TS circRNAs are generated from exonic regions. To further understand the potential functions of TS circRNAs, we identified microRNAs and RNA binding protein, which might bind to TS circRNAs. This process suggested their involvement in development and organ differentiation. Finally, we constructed an integrated database TSCD (Tissue-Specific CircRNA Database: http://gb.whu.edu.cn/TSCD) to deposit the features of TS circRNAs. This study is the first comprehensive view of TS circRNAs in human and mouse, which shed light on circRNA functions in organ development and disorders.

/pdf/comprehensive-characterization-of-tissue-specific-circular-2e2e9a4myt.pdf

Comprehensive characterization of tissue-specific circular RNAs in the human and mouse genomes

Long Stokes shift dyes that minimize cross-talk between the excitation source and fluorescent emission to improve the signal-to-background ratio are highly desired for fluorescence imaging. However, simple small molecular dyes with large Stokes shift (more than 120 nanometers) and near-infrared (NIR) emissions have been rarely reported so far. Here, inspired by the chromophore chemical structure of fluorescent proteins, we designed and synthesized a series of styrene oxazolone dyes (SODs) with simple synthetic methods, which show NIR emissions (>650 nanometers) with long Stokes shift (ranged from 136 to 198 nanometers) and small molecular weight (<450 daltons). The most promising SOD9 shows rapid renal excretion and blood-brain barrier passing properties. After functioning with the mitochondrial-targeted triphenylphosphonium (TPP) group, the resulting SOD9-TPP can be engineered for head-neck tumor imaging, fluorescence image–guided surgery, brain neuroimaging, and on-site pathologic analysis. In summary, our findings add an essential small molecular dye category to the classical dyes.

Bioinspired large Stokes shift small molecular dyes for biomedical fluorescence imaging

Tumor-targeted and stimuli-activatable nanosensitizers are highly desirable for cancer theranostics. However, design of smart nanosensitizers with multiple imaging signals and synergistic therapeutic activities switched on is challenging. Herein, we report tumor-targeted and redox-activatable nanosensitizers (1-NPs) for sono-photodynamic immunotherapy of tumors by molecular co-assembly and redox-controlled disassembly. 1-NPs show a high longitudinal relaxivity (r1 = 18.7 ± 0.3 mM-1 s-1), but "off" dual fluorescence (FL) emissions (at 547 and 672 nm), "off" sono-photodynamic therapy and indoleamine 2,3-dioxygenase 1 (IDO1) inhibition activities. Upon reduction by glutathione (GSH), 1-NPs rapidly disassemble and remotely release small molecules 2-Gd, Zn-PPA-SH and NLG919, concurrently switching on (1) dual FL emissions, (2) sono-photodynamic therapy and (3) IDO1 inhibition activities. After systemic injection, 1-NPs are effective for bimodal FL and magnetic resonance (MR) imaging-guided sono-photodynamic immunotherapy of orthotropic breast and brain tumors in mice under combined ultrasound (US) and 671-nm laser irradiation.

Smart Nanosensitizers for Activatable Sono-Photodynamic Immunotherapy of Tumors by Redox-Controlled Disassembly.

Controlling delivery and release of therapeutic agents to accomplish on-demand synergistic therapy of orthotopic gliomas is desired but challenging. Here, we report a glioma targeting and redox activatable theranostic nanoprobe (Co-NP-RGD1/1) for magnetic resonance (MR) and fluorescence (FL) bimodal imaging-guided on-demand synergistic chemotherapy/photodynamic therapy (Chemo-PDT) of orthotopic gliomas. Co-NP-RGD1/1 is formed via molecular coassembly of two paramagnetic and fluorogenic small-molecule probes CPT-RGD and PPa-RGD at an optimized molar ratio of 1/1, which shows a high longitudinal relaxivity (r1 = 17.0 ± 0.6 mM-1 s-1, 0.5 T) but weak FL emissions and low Chemo-PDT activity. Upon reduction by endogenous glutathione (GSH), Co-NP-RGD1/1 disassemble and release small molecules 2-RGD, chemodrug camptothecin (CPT), and near-infrared (NIR) photosensitizer (PS) PPa-SH that further binds to endogenous albumin to form PPa-SH-albumin complex, allowing to turn on FL, chemotherapeutic efficacy, and PDT activity for synergistic Chemo-PDT of orthotopic U87MG or U251 gliomas in living mice. Moreover, Co-NP-RGD1/1 can also allow noninvasive detection and monitoring of orthotopic brain tumor growth via FL and MR imaging. Findings suggest the potential of cascade coassembly and stimuli-controlled intracellular disassembly strategy for constructing targeted and activatable nanoagents for improving combinational cancer theranostics.

Controlling Disassembly of Paramagnetic Prodrug and Photosensitizer Nanoassemblies for On-Demand Orthotopic Glioma Theranostics.

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Comprehensive characterization of tissue-specific circular RNAs in the human and mouse genomes

Bioinspired large Stokes shift small molecular dyes for biomedical fluorescence imaging

Smart Nanosensitizers for Activatable Sono-Photodynamic Immunotherapy of Tumors by Redox-Controlled Disassembly.

Controlling Disassembly of Paramagnetic Prodrug and Photosensitizer Nanoassemblies for On-Demand Orthotopic Glioma Theranostics.