The role of microRNA in the delayed negative feedback regulation of gene expression

Oscillatory gene expression plays an important role in somite segmentation during the early developmental stages of vertebrates. Recent experimental studies have shown that microRNA can regulate gene expression by stimulating degradation of mRNA and/or repression of translation. In this communication, we incorporate miRNA into a previous mathematical model of gene expression with delayed negative feedback and demonstrate how this modified model can elucidate the possible effect of miRNA on the oscillatory gene expression. Our finding suggests that miRNA maybe a destabilizing or stabilizing factor in the dynamics of gene expression depending on the severity of its effect on mRNA degradation. Our finding provides testable hypothesis for experimental biologists to further investigate miRNA's increasing functional roles in regulating cellular processes and development.     

Modeling of miRNA and drug action in the EGFR signaling pathway

MicroRNAs have gained significant interest due to their widespread occurrence and diverse functions as regulatory molecules, which are essential for cell division, growth, development and apoptosis in eukaryotes. The epidermal growth factor receptor (EGFR) signaling pathway is one of the best investigated cellular signaling pathways regulating important cellular processes and its deregulation is associated with severe diseases, such as cancer. In this study, we introduce a systems biological model of the EGFR signaling pathway integrating validated miRNA-target information according to diverse studies, in order to demonstrate essential roles of miRNA within this pathway. The model consists of 1241 reactions and contains 241 miRNAs. We analyze the impact of 100 specific miRNA inhibitors (anit-miRNAs) on this pathway and propose that the embedded miRNA-network can help to identify new drug targets of the EGFR signaling pathway and thereby support the development of new therapeutic strategies against cancer.     

MicroRNAs in the shoot apical meristem of soybean

Plant microRNAs (miRNAs) play crucial regulatory roles in various developmental processes. In this study, we characterize the miRNA profile of the shoot apical meristem (SAM) of an important legume crop, soybean, by integrating high-throughput sequencing data with miRNA microarray analysis. A total of 8423 non-redundant sRNAs were obtained from two libraries derived from micro-dissected SAM or mature leaf tissue. Sequence analysis allowed the identification of 32 conserved miRNA families as well as 8 putative novel miRNAs. Subsequent miRNA profiling with microarrays verified the expression of the majority of these conserved and novel miRNAs. It is noteworthy that several miRNAs* were expressed at a level similar to or higher than their corresponding mature miRNAs in SAM or mature leaf, suggesting a possible biological function for the star species. In situ hybridization analysis revealed a distinct spatial localization pattern for a conserved miRNA, miR166, and its star speciessuggesting that they serve different roles in regulating leaf development. Furthermore, localization studies showed that a novel soybean miRNA, miR4422a, was nuclear-localized. This study also indicated a novel expression pattern of miR390 in soybean. Our approach identified potential key regulators and provided vital spatial information towards understanding the regulatory circuits in the SAM of soybean during shoot development.     

Computational analysis of drought stress-associated miRNAs and miRNA co-regulation network in Physcomitrella patens

miRNAs are non-coding small RNAs that involve diverse biological processes. Until now, little is known about their roles in plant drought resistance. Physcomitrella patens is highly tolerant to drought; however, it is not clear about the basic biology of the traits that contribute P. patens this important character. In this work, we discovered 16 drought stress-associated miRNA (DsAmR) families in P. patens through computational analysis. Due to the possible discrepancy of expression periods and tissue distributions between potential DsAmRs and their targeting genes, and the existence of false positive results in computational identification, the prediction results should be examined with further experimental validation. We also constructed an miRNA co-regulation network, and identified two network hubs, miR902a-5p and miR414, which may play important roles in regulating drought-resistance traits. We distributed our results through an online database named ppt-miRBase, which can be accessed at http://bioinfor.cnu.edu.cn/ppt_miRBase/index.php. Our methods in finding DsAmR and miRNA co-regulation network showed a new direction for identifying miRNA functions.     

睾丸发育和精子生成相关miRNA研究进展

MicroRNA(miRNA)是一类长约22nt的非编码小RNA, 广泛存在于各种生物中, 调节生物体生长、发育和凋亡等过程。研究表明, miRNA在人和动物睾丸发育及精子生成等过程也起着重要的调控作用。但miRNA在不同种属的睾丸组织及其不同发育时间段均存在特异性表达。此外, miRNA在动物精子生成过程中也存在时空特异性。文章综述了睾丸发育和精子生成过程中miRNA的差异性表达、表达调控以及一些miRNA对精子生成的调节作用, 旨在为睾丸miRNA的进一步研究提供参考, 为利用miRNA调控和促进种公畜精液品质提供研究思路。     

A strategy to rapidly identify the functional targets of microRNAs by combining bioinformatics and mRNA cytoplasmic/nucleic ratios in culture cells

MicroRNAs are approximately 22nt non-coding RNAs that are present in a broad range of multicellular organisms. MicroRNAs play important roles in many biological or pathological processes by regulating the expression of their target genes. The fast and accurate identification of miRNA targets is a bottleneck in the clarification of the function of miRNAs. Here, we established a rapid and accurate strategy to identify miRNA functional target genes by combination of bioinformatic prediction with Cytoplasmic/Nuclear (C/N) ratios of mRNAs. The strategy comprises three steps: bioinformatic prediction, determination of mRNA C/N ratios, and confirmation by Western blotting, and might be suitable to most miRNAs. Our method will make a significant contribution to the study of the biological functions of miRNAs.     

Tau/DDX6 interaction increases microRNA activity

Tauopathies, such as Alzheimer's disease, are characterized by intracellular aggregates of insoluble Tau proteins. Originally described as a microtubule binding protein, recent studies demonstrated additional physiological roles for Tau. The fact that a single protein can regulate multiple cellular functions has posed challenge in terms of understanding mechanistic cues behind the pathology. Here, we used tandem-affinity purification methodology coupled to mass spectrometry to identify novel interaction partners. We found that Tau interacts with DDX6, a DEAD box RNA helicase involved in translation repression and mRNA decay as well as in the miRNA pathway. Our results demonstrate that Tau increases the silencing activity of the miRNA let-7a, miR-21 and miR-124 through DDX6. Importantly, Tau mutations (P301S, P301L) found in the inherited tauopathies, frontotemporal dementia and parkinsonism linked to chromosome 17, disrupt Tau/DDX6 interaction and impair gene silencing by let-7a. Altogether, these data demonstrated a new unexpected role for Tau in regulating miRNA activity.     

Dynamic microRNAome profiles in the developing porcine liver

Increasing evidence suggests that micro (mi)RNAs play important roles in various biological process. To evaluate the roles of miRNA in the porcine liver, we investigated the dynamic profiles of microRNAomes using liver tissue from pigs during the embryonic period (embryonic day 90), weaning stage (postnatal day 30), and adult stage (7 years old). A total of 186 unique miRNAs were differentially expressed during liver development. We also identified that 17, 13, and 6 miRNAs were specifically abundant at embryonic day 90, postnatal day 30, and at 7 years, respectively. Besides regulating basic cellular roles in development, miRNAs expressed at the three developmental stages also participated in regulating “embryonic liver development,” “early hepatic growth and generating a functioning liver,” and “energy metabolic processes,” respectively. Our study indicates that miRNAs are extensively involved in liver development, and provides a valuable resource for the further elucidation of miRNA regulatory roles during liver development.     

Evolutionary conservation of microRNA regulatory circuits: an examination of microRNA gene complexity and conserved microRNA-target interactions through metazoan phylogeny

During the last decade, a variety of critical biological processes, including early embryo development, cell proliferation, differentiation, apoptosis, and metabolic regularity, have been shown to be genetically regulated by a large gene family encoding a class of tiny RNA molecules termed microRNAs (miRNAs). All miRNAs share a common biosynthetic pathway and reaction mechanisms. The sequence of many miRNAs is found to be conserved, in their mature form, among different organisms. In addition, the evolutionary appearance of multicellular organisms appears to correlate with the appearance of the miRNA pathway for regulating gene expression. The miRNA pathway has the potential to regulate vast networks of gene products in a coordinate manner. Recent evidence has not only implicated the miRNA pathway in regulating a vast array of basic cellular processes but also specialized processes that are required for cellular identity and tissue specificity. A survey of the literature shows that some miRNA pathways are conserved virtually intact throughout phylogeny while miRNA diversity also correlates with speciation. The number of miRNA genes, the expression of miRNAs, and target diversities of miRNAs tend to be positively correlated with morphological complexities observed in animals. Thus, organismal complexity can be estimated by the complexity of the miRNA circuitry. The complexity of the miRNA gene families establishes a link between genotypic complexity and phenotypic complexity in animal evolution. In this paper, we start with the discussion of miRNA conservation. Then we interpret the trends in miRNA conservation to deduce miRNA evolutionary trends in metazoans. Based on these conservation patterns observed in each component of the miRNA regulatory system, we attempt to propose a global insight on the probable consistency between morphological evolution in animals and the molecular evolution of miRNA gene activity in the cell.     

The evolution of animal microRNA function

MicroRNAs (miRNAs) are a large class of small RNAs that function as negative gene regulators in eukaryotes. They regulate diverse biological processes, and bioinformatics data indicate that each miRNA can control hundreds of gene targets, underscoring the potential influence of miRNAs on almost every genetic pathway. In addition to the roles in ontogeny, recent evidence has suggested the possibility that miRNAs have huge impacts on animal phylogeny. The dramatically expanding repertoire of miRNAs and their targets appears to be associated with major body-plan innovations as well as the emergence of phenotypic variation in closely related species. Research in the area of miRNA phylogenetic conservation and diversity suggests that miRNAs play important roles in animal evolution, by driving phenotypic variation during development.     

Iron homeostasis regulates the activity of the microRNA pathway through poly(C)-binding protein 2

MicroRNAs (miRNAs) control gene expression by promoting degradation or repressing translation of target mRNAs. The components of the miRNA pathway are subject to diverse modifications that can modulate the abundance and function of miRNAs. Iron is essential for fundamental metabolic processes, and its homeostasis is tightly regulated. Here we identified iron chelators as a class of activator of the miRNA pathway that could promote the processing of miRNA precursors. We show that cytosolic iron could regulate the activity of the miRNA pathway through poly(C)-binding protein 2 (PCBP2). PCBP2 is associated with Dicer and promotes the processing of miRNA precursors. Cytosolic iron could modulate the association between PCBP2 and Dicer, as well as the multimerization of PCBP2 and its ability to bind to miRNA precursors, which can alter the processing of miRNA precursors. Our findings reveal a role of iron homeostasis in the regulation of miRNA biogenesis.