Insight into animal biology and development provided by classical genetic analysis of the model organism Drosophila melanogaster was an incentive to develop advanced genetic tools for this insect. But genetic systems for the over one million other known insect species are largely undeveloped. With increasing information about insect genomes resulting from next generation sequencing, RNA interference is now the method of choice for reverse genetics, although it is constrained by the means of delivery of interfering RNA. A recent advance (...) to ensure sustained delivery with minimal experimental intervention or trauma to the insect is to exploit commensal bacteria for symbiont‐mediated RNA interference. This technology not only offers an efficient means for RNA interference in insects in laboratory conditions, but also has potential for use in the control of human disease vectors, agricultural pests and pathogens of beneficial insects. (shrink)

In eukaryotes, double‐stranded RNAs (dsRNAs) or short, interfering dsRNAs (siRNAs) can reduce the accumulation of a sequence‐related mRNA, often resulting in a loss‐of‐function phenotype—a process termed RNA interference (RNAi). Unfortunately, some mRNAs are resistant to the effects of dsRNA. Experiments designed to unravel RNAi mechanisms in Caenorhabditis elegans have led to the identification of two worm proteins, RRF‐31,2 and, now, ERI‐1,3 that can inhibit RNAi responses. Animals defective in either protein can display enhanced RNAi phenotypes for mRNAs that were (...) previously resistant to dsRNA. Since ERI‐1 is a conserved protein, development of procedures to enhance RNAi effectiveness in other systems may be possible. BioEssays 26:715–718, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin‐converting enzyme (ACE) is the central component of endocrine and local tissue renin–angiotensin systems (RAS), which also regulate diverse aspects of whole‐body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3‐55C (rather than (...) T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P < 0·01) whilst increasing ACE expression within a physiological range (<1·8‐fold at 48 h; P < 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role. (shrink)

Much research has focused on the effects of pathogenic mitochondrial mutations on health. Notwithstanding, the mechanisms regulating the link between these mutations and their effects remain elusive in several cases. Here, we propose that certain mitochondrial mutations may disrupt function of a set of mitochondrial‐transcribed small RNAs, perturbing communication between mitochondria and nucleus, leading to disease. Our hypothesis synthesises two lines of supporting evidence. First, several mitochondrial mutations cannot be directly linked to effects on energy production or protein synthesis. Second, (...) emerging studies have described the existence of small RNAs encoded by the mitochondria and proposed their involvement in RNA interference. We present a roadmap to testing this hypothesis. (shrink)

The discovery of RNA interference in 1998 has made a lasting impact on biological research. Identifying the regulatory role of small RNAs changed the modes of molecular biological inquiry as well as biologists' understanding of genetic regulation. This article examines the early years of small RNA biology's success story. I query which factors had to come together so that small RNA research came into life in the blink of an eye. I primarily look at scientific repertoires as facilitators of (...) rapid scientific change. I show that for a short period of time, between the years 1998 and 2002, different model organism communities, investigative strategies, technological innovations, and research interests could be successfully aligned to take small RNA research off the ground. I discuss how the keystone discoveries were situated in specific experimental traditions and what strategies were employed to establish these discoveries as more general phenomena. Providing thus a practice-based approach of rapid scientific change, I ask how to relate the change in propositional bits of scientific knowledge with changes in scientific practice. (shrink)

Heritable traits are predominantly encoded within genomic DNA, but it is now appreciated that epigenetic information is also inherited through DNA methylation, histone modifications, and small RNAs. Several examples of transgenerational epigenetic inheritance of traits have been documented in plants and animals. These include even the inheritance of traits acquired through the soma during the life of an organism, implicating the transfer of epigenetic information via the germline to the next generation. Small RNAs appear to play a significant role in (...) carrying epigenetic information across generations. This review focuses on how epigenetic information in the form of small RNAs is transmitted from the germline to the embryos through the gametes. We also consider how inherited epigenetic information is maintained across generations in a small RNA‐dependent and independent manner. Finally, we discuss how epigenetic traits acquired from the soma can be inherited through small RNAs. (shrink)

Dicer is a key player in microRNA (miRNA) and RNA interference (RNAi) pathways, processing miRNA precursors and doublestranded RNA into ~21-nt-long products ultimately triggering sequence-dependent gene silencing. Although processing of substrates in vertebrate cells occurs in the cytoplasm, there is growing evidence suggesting Dicer is also present and functional in the nucleus. To address this possibility, we searched for a nuclear localization signal (NLS) in human Dicer and identified its C-terminal double-stranded RNA binding domain (dsRBD) as harboring NLS activity. (...) We show that the dsRBD-NLS can mediate nuclear import of a reporter protein via interaction with importins β, 7, and 8. In the context of full-length Dicer, the dsRBD-NLS is masked. However, duplication of the dsRBD localizes the full-length protein to the nucleus. Furthermore, deletion of the N-terminal helicase domain results in partial accumulation of Dicer in the nucleus upon leptomycin B treatment, indicating that CRM1 contributes to nuclear export of Dicer. Finally, we demonstrate that human Dicer has the ability to shuttle between the nucleus and the cytoplasm. We conclude that Dicer is a shuttling protein whose steady-state localization is cytoplasmic. (shrink)

X inactivation is the process that brings about the dosage equivalence of X‐linked genes in females to that of males. This complex process initiated at a very early stage of female embryonic development is orchestrated by long non‐coding RNAs transcribed in both sense and antisense orientation. Recent studies present contradicting evidence for the role of small RNAs and RNase III enzyme Dicer in the X inactivation process. In this review, I discuss these results in the overall perspective of X inactivation (...) and gene silencing. (shrink)

Heterochronic genes control the timing of developmental programs. In C. elegans, two key genes in the heterochronic pathway, lin-4 and let-7, encode small temporally expressed RNAs (stRNAs) that are not translated into protein. These stRNAs exert negative post-transcriptional regulation by binding to complementary sequences in the 3′ untranslated regions of their target genes. stRNAs are transcribed as longer precursor RNAs that are processed by the RNase Dicer/DCR-1 and members of the RDE-1/AGO1 family of proteins, which are better known for their (...) roles in RNA interference (RNAi). However, stRNA function appears unrelated to RNAi. Both sequence and temporal regulation of let-7 stRNA is conserved in other animal species suggesting that this is an evolutionarily ancient gene. Indeed, C. elegans, Drosophila and humans encode at least 86 other RNAs with similar structural features to lin-4 and let-7. We postulate that other small non-coding RNAs may function as stRNAs to control temporal identity during development in C. elegans and other organisms. BioEssays 24:119–129, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The multiplicity of deubiquitinating enzymes (DUBs) encoded by vertebrate genomes is partly attributable to whole genome duplication events that occurred early in chordate evolution. By surveying the literature for the largest family of DUBs (the ubiquitin-specific proteases), extensive functional redundancy for duplicated genes has been confirmed as opposed to singletons. Dramatically conflicting results have been reported for loss of function studies conducted through RNA interference as opposed to inactivating mutations, but the contradictory findings can be reconciled by a recently (...) proposed compensatory mechanism involving nonsense-mediated RNA degradation. Duplicated genes are often inactivated to become pseudogenes, and it is proposed that such is the fate of the USP15 gene of zebrafish, a commonly used model system. As it is reviewed here, these observations have implications not only for the interpretation of model system phenotypes but also for therapeutic interventions designed to target DUBs. (shrink)

In human cancers, histone methyltransferase SETDB1 (SET domain, bifurcated 1) is frequently overexpressed but its significance in carcinogenesis remains elusive. A recent study shows that SETDB1 downregulation induces de‐repression of retroelements and innate immunity in cancer cells. The possibility of SETDB1 functioning as a surveillant of retroelement expression is discussed in this study: the cytoplasmic presence of retroelement‐derived nucleic acids (RdNAs) drives SETDB1 into the nucleus by the RNA‐interference route, rendering the corresponding retroelement transcriptionally inert. These RdNAs could, therefore, (...) be signals of genome instability sent out for SETDB1 present in the cytoplasm to maintain genome integrity. (shrink)

Evolution is frequently concentrated in bursts of rapid morphological change and speciation followed by long‐term stasis. We propose that this pattern of punctuated equilibria results from an evolutionary tug‐of‐war between host genomes and transposable elements (TEs) mediated through the epigenome. According to this hypothesis, epigenetic regulatory mechanisms (RNA interference, DNA methylation and histone modifications) maintain stasis by suppressing TE mobilization. However, physiological stress, induced by climate change or invasion of new habitats, disrupts epigenetic regulation and unleashes TEs. With their (...) capacity to drive non‐adaptive host evolution, mobilized TEs can restructure the genome and displace populations from adaptive peaks, thus providing an escape from stasis and generating genetic innovations required for rapid diversification. This “epi‐transposon hypothesis” can not only explain macroevolutionary tempo and mode, but may also resolve other long‐standing controversies, such as Wright's shifting balance theory, Mayr's peripheral isolates model, and McClintock's view of genome restructuring as an adaptive response to challenge. (shrink)

Eukaryotic gene expression is extensively controlled at the level of mRNA stability and the mechanisms underlying this regulation are markedly different from their archaeal and bacterial counterparts. We propose that two such mechanisms, nonsense‐mediated decay (NMD) and motif‐specific transcript destabilization by CCCH‐type zinc finger RNA‐binding proteins, originated as a part of cellular defense against RNA pathogens. These branches of the mRNA turnover pathway might have been used by primeval eukaryotes alongside RNA interference to distinguish their own messages from those (...) of RNA viruses and retrotransposable elements. We further hypothesize that the subsequent advent of “professional” innate and adaptive immunity systems allowed NMD and the motif‐triggered mechanisms to be efficiently repurposed for regulation of endogenous cellular transcripts. This scenario explains the rapid emergence of archetypical mRNA destabilization pathways in eukaryotes and argues that other aspects of post‐transcriptional gene regulation in this lineage might have been derived through a similar exaptation route. -/- . (shrink)

This aricle discusses the similarity between the propagation of pathogens (viruses and worms) on computer networks and the proliferation of pathogens in cellular organisms (organisms with genetic material contained within a membrane-encased nucleus). It introduces several biological mechanisms which are used in these organisms to protect against such pathogens and presents security models for networked computers inspired by several biological paradigms, including genomics (RNA interference), proteomics (pathway mapping), and physiology (immune system). In addition, the study of epidemiological models for (...) disease control can inspire methods for controlling the spread of pathogens across multiple nodes of a network. It also presents results based on the authors’ research in immune system modeling. (shrink)

In three recent articles it was shown that β‐catenin is crucial for the establishment and the maintenance of the overall polarity and especially for the character ‘posterior’ in planarians. If the transcription of the β‐catenin gene was silenced by RNA interference, the overall polarity is lost, and in regenerating fragments a posterior blastema displays anterior characters by forming eyes and anterior ganglia. An attempt is made to integrate these new data, well‐known older observations, and observations from other regenerating systems (...) into an outline of a model that will clarify our current understanding as well as highlight areas still to be developed. (shrink)

Invertebrate genetic models with their tractable neuromuscular systems are effective vehicles for the study of human nerve and muscle disorders. This is exemplified by insights made into spinal muscular atrophy (SMA) using the fruit fly Drosophila melanogaster and the nematode worm Caenorhabditis elegans. For speed and economy, these invertebrates offer convenient, whole‐organism platforms for genetic screening as well as RNA interference (RNAi) and chemical library screens, permitting the rapid testing of hypotheses related to disease mechanisms and the exploration of (...) new therapeutic routes and drug candidates. Here, we discuss recent developments encompassing synaptic physiology, RNA processing, and screening of compound and genome‐scale RNAi libraries, showcasing the importance of invertebrate SMA models.Editor's suggested further reading in BioEssays: SMN and Gemins: ‘We are family’... or are we? Abstract. (shrink)

If validated, diet‐derived foreign microRNA absorption and function in consuming vertebrates would drastically alter our understanding of nutrition and ecology. RNA interference (RNAi) mechanisms of Caenorhabditis elegans are enhanced by uptake of environmental RNA and amplification and systemic distribution of RNAi effectors. Therapeutic exploitation of RNAi in treating human disease is difficult because these accessory processes are absent or diminished in most animals. A recent report challenged multiple paradigms, suggesting that ingested microRNAs (miRNAs) are transferred to blood, accumulate in (...) tissues, and exert canonical regulation of endogenous transcripts. Independent replication of these findings has been elusive, and multiple disconfirmatory findings have been published. In the face of mounting negative results, any additional positive reports must provide the proverbial “extraordinary proof” to support such claims. In this article, we review the evidence for and against a significant role for dietary miRNAs in influencing gene expression, and make recommendations for future studies.Also watch the Video Abstract. (shrink)

The last decade has seen a dramatic increase in interest in the extent to which morphological evolution depends on changes in regulatory pathways. Insects provide a fertile ground for study because of their diversity and our high level of understanding of the genetic regulation of development in Drosophila melanogaster. However, comparable genetic approaches are presently possible in only a small number of non‐Drosophilid insects. In a recent paper, Hughes and Kaufman(1) have used a new methodology, RNA interference, in the (...) milkweed bug, Oncopeltus fasciatus, to phenocopy the effects of mutations in Hox genes. RNA interference involves the injection of double‐stranded RNA of the same sequence as the relevant mRNA resulting in a depletion of that transcript.(2) Hughes and Kaufman focused on the gnathal segments, which elaborate specialized appendages important to feeding. Their results indicate that gnathal adaptations in this bug are correlated with changes in Hox gene functions and interactions. BioEssays 23:379–382, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The centromere is the region of the chromosome where the kinetochore forms. Kinetochores are the attachment sites for spindle microtubules that separate duplicated chromosomes in mitosis and meiosis. Kinetochore formation depends on a special chromatin structure containing the histone H3 variant CENP‐A. The epigenetic mechanisms that maintain CENP‐A chromatin throughout the cell cycle have been studied extensively but little is known about the mechanism that targets CENP‐A to naked centromeric DNA templates. In a recent report published in Science,1 such de (...) novo centromere assembly of CENP‐A is shown to be dependent on heterochromatin and the RNA interference pathway. BioEssays 30:526–529, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Scientific anomalies are observations and facts that contradict current scientific theories and they are instrumental in scientific theory change. Philosophers of science have approached scientific theory change from different perspectives as Darden (Theory change in science: Strategies from Mendelian genetics, 1991) observes: Lakatos (In: Lakatos, Musgrave (eds) Criticism and the growth of knowledge, 1970) approaches it as a progressive “research programmes” consisting of incremental improvements (“monster barring” in Lakatos, Proofs and refutations: The logic of mathematical discovery, 1976), Kuhn (The structure (...) of scientific revolutions, 1996) observes that changes in “paradigms” are instigated by a crisis from some anomaly, and Hanson (In: Feigl, Maxwell (eds) Current issues in the philosophy of science, 1961) proposes that discovery does not begin with hypothesis but with some “problematic phenomena requiring explanation”. Even though anomalies are important in all of these approaches to scientific theory change, there have been only few investigations into the specific role anomalies play in scientific theory change. Furthermore, much of these approaches focus on the theories themselves and not on how the scientists and their experiments bring about scientific change (Gooding, Experiment and the making of meaning: Human agency in scientific observation and experiment, 1990). To address these issues, this paper approaches scientific anomaly resolution from a meaning construction point of view. Conceptual integration theory (Fauconnier and Turner, Cogn Sci 22:133–187, 1996; The way we think: Conceptual blending and mind’s hidden complexities, 2002) from cognitive linguistics describes how one constructs meaning from various stimuli, such as text and diagrams, through conceptual integration or blending. The conceptual integration networks that describe the conceptual integration process characterize cognition that occurs unconsciously during meaning construction. These same networks are used to describe some of the cognition while resolving an anomaly in molecular genetics called RNA interference (RNAi) in a case study. The RNAi case study is a cognitive-historical reconstruction (Nersessian, In: Giere (ed) Cognitive models of science, 1992) that reconstructs how the RNAi anomaly was resolved. This reconstruction traces four relevant molecular genetics publications in describing the cognition necessary in accounting for how RNAi was resolved through strategies (Darden 1991), abductive reasoning (Peirce, In: Hartshorne, Weiss (eds) Collected papers, 1958), and experimental reasoning (Gooding 1990). The results of the case study show that experiments play a crucial role in formulating an explanation of the RNAi anomaly and the integration networks describe the experiments’ role. Furthermore, these results suggest that RNAi anomaly resolution is embodied. It is embodied in a sense that cognition described in the cognitive-historical reconstruction is experientially based. (shrink)

Mammalian synthetic biology holds the promise of providing novel therapeutic strategies, and the first success stories are beginning to be reported. Here we focus on the latest generation of mammalian transgene control devices, highlight state‐of‐the‐art synthetic gene network design, and cover prototype therapeutic circuits. These will have an impact on future gene‐ and cell‐based therapies and help bring drug discovery into a new era. The inventory of biological parts that are essential for life on this planet is becoming increasingly complete. (...) The postgenomic era has provided encyclopedic information on gene‐function correlations and systems biology is now delivering comprehensive details on the dynamics of biochemical reaction networks in living organisms. The time has come to reassemble these catalogued items and design new biological devices and systems with novel and useful functionality in a rational and systematic manner. This is the premise of synthetic biology, a constructive systems biology discipline likely to become the life science revolution of the 21st century. (shrink)

Cryo‐electron microscopy allows the visualization of macromolecules in their native state. Combined with techniques of three‐dimensional reconstruction, cryo‐EM images of single molecules can be used to study macromolecular interactions. The ribosome, a large RNA–protein complex with multiple binding interactions, is an excellent test case illustrating the power of these new techniques. Conformational changes during the binding of tRNA and protein factors to the ribosome can now be studied without the interference of crystal packing. Now that the first X‐ray structures (...) of ribosomal subunits have become available, conformational changes observed by cryo‐EM in different functional states can be traced back to internal rearrangements of the underlying structural framework. Electron microscopy, X‐ray crystallography, and modeling should be used together in the endeavor to understand the functioning of the translational machinery. BioEssays 23:725–732, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

This paper follows the circuitous path of theories concerning the origins of viruses from the early years of the twentieth century until the present, considering RNA viruses in particular. I focus on three periods during which new understandings of the nature of viruses guided the construction and reconstruction of origin hypotheses. During the first part of the twentieth century, viruses were mostly viewed from within the framework of bacteriology and the discussion of origin centered on the “degenerative” or the “retrograde (...) evolution theory.” However, concomitantly, in the context of origin-of-life theorizing, the notion that viruses are vestiges of a prebiotic world was also being contemplated. In the 1960s the idea that viruses were genetic elements that “escaped” from cells became prevalent. These traditional hypotheses are being revisited nowadays by evolutionary virologists, who have placed them within a new conceptual framework that is supported by cutting-edge genomic and proteomic data. Two current, opposing scenarios of virus origin are presented. The philosophical dimensions of “revisiting” the original hypotheses are briefly discussed. (shrink)

Membranous organelles allow sub‐compartmentalization of biological processes. However, additional subcellular structures create dynamic reaction spaces without the need for membranes. Such membrane‐less organelles (MLOs) are physiologically relevant and impact development, gene expression regulation, and cellular stress responses. The phenomenon resulting in the formation of MLOs is called liquid–liquid phase separation (LLPS), and is primarily governed by the interactions of multi‐domain proteins or proteins harboring intrinsically disordered regions as well as RNA‐binding domains. Although the presence of RNAs affects the formation and (...) dissolution of MLOs, it remains unclear how the properties of RNAs exactly contribute to these effects. Here, the authors review this emerging field, and explore how particular RNA properties can affect LLPS and the behavior of MLOs. It is suggested that post‐transcriptional RNA modification systems could be contributors for dynamically modulating the assembly and dissolution of MLOs. (shrink)

High‐fidelity binding of transcription factors (TFs) to DNA target sites is fundamental for proper regulation of cellular processes, as well as for the maintenance of cell identity. Recognition of cognate binding motifs in the genome is attributed by and large to the DNA binding domains of TFs. As an additional mode of conferring binding specificity, noncoding RNAs (ncRNAs) have been proposed to assist associated TFs in finding their binding sites by interacting with either DNA or RNA in the vicinity of (...) their target loci. However, a well‐documented example of such a mechanism was lacking until we recently reported that a ncRNA made by Epstein‐Barr virus uses an RNA–RNA interaction with nascent transcripts generated from the viral genome to facilitate the recruitment of an interacting TF, PAX5, to viral DNA. This proof‐of‐principle finding suggests that cellular ncRNAs may likewise function in guiding interacting TFs to chromatin target sites. (shrink)

Eukaryotic mRNAs are monocistronic, and therefore mechanisms exist that coordinate the synthesis of multiprotein complexes in order to obtain proper stoichiometry at the appropriate intracellular locations. RNA‐binding proteins containing low‐complexity sequences are prone to generate liquid droplets via liquid‐liquid phase separation, and in this way create cytoplasmic assemblages of functionally related mRNAs. In a recent iCLIP study, we showed that the Drosophila RNA‐binding protein Imp, which exhibits a C‐terminal low‐complexity sequence, increases the formation of F‐actin by binding to 3′ untranslated (...) regions of mRNAs encoding components participating in F‐actin biogenesis. We hypothesize that phase transition is a mechanism the cell employs to increase the local mRNA concentration considerably, and in this way synchronize protein production in cytoplasmic territories, as discussed in the present review. (shrink)

RNA polymerase II is recruited to DNA double‐strand breaks (DSBs), transcribes the sequences that flank the break and produces a novel RNA type that has been termed damage‐induced long non‐coding RNA (dilncRNA). DilncRNAs can be processed into short, miRNA‐like molecules or degraded by different ribonucleases. They can also form double‐stranded RNAs or DNA:RNA hybrids. The DNA:RNA hybrids formed at DSBs contribute to the recruitment of repair factors during the early steps of homologous recombination (HR) and, in this way, contribute to (...) the accuracy of the DNA repair. However, if not resolved, the DNA:RNA hybrids are highly mutagenic and prevent the recruitment of later HR factors. Here recent discoveries about the synthesis, processing, and degradation of dilncRNAs are revised. The focus is on RNA clearance, a necessary step for the successful repair of DSBs and the aim is to reconcile contradictory findings on the effects of dilncRNAs and DNA:RNA hybrids in HR. (shrink)

In his Target Article, Terrence Deacon develops simple models that assist in understanding the role of RNA in the origins of life. However, his models fail to adequately represent an important evolutionary dynamic. Central to this dynamic is the selection that impinges on RNA molecules in the context of their association with proto-metabolisms. This selection shapes the role of RNA in the emergence of life. When this evolutionary dynamic is appropriately taken into account, it predicts a role for RNA that (...) is consistent with the Managed-Metabolism Hypothesis about the origins of life, and inconsistent with Deacon’s account. (shrink)

Changes in the abundance of protein and RNA molecules can impair the formation of complexes in the cell leading to toxicity and death. Here we exploit the information contained in protein, RNA and DNA interaction networks to provide a comprehensive view of the regulation layers controlling the concentration‐dependent formation of assemblies in the cell. We present the emerging concept that RNAs can act as scaffolds to promote the formation ribonucleoprotein complexes and coordinate the post‐transcriptional layer of gene regulation. We describe (...) the structural and interaction network properties that characterize the ability of protein and RNA molecules to interact and phase separate in liquid‐like compartments. Finally, we show that presence of structurally disordered regions in proteins correlate with the propensity to undergo liquid‐to‐solid phase transitions and cause human diseases. Also see the video abstract here https://youtu.be/kfpqibsNfS0. (shrink)

Masks, interferers, finks, reverse finks, and mimickers are troublesome for powers metaphysics insofar as the latter concedes that there are powers with essential stimuli/activation conditions. In this article, I aim at offering a novel approach for solving this problem. In Section 1, I shall present the problem; and in Section 2, I shall briefly show how it also arises within non‐reductive views of powers. Subsequently, in Section 3, I shall examine the failure of the ceteris paribus solution. The pars construens (...) will begin in Section 4, where I shall distinguish between the activation conditions, the background conditions, and the possession conditions of a power. Within each category, I shall draw further distinctions. In Section 5, I shall demonstrate how such distinctions may ground a solution to our problem. Finally, in Section 6, I shall anticipate and reply to four objections. (shrink)

There is increasing evidence that dynamic changes to chromatin, chromosomes and nuclear architecture are regulated by RNA signalling. Although the precise molecular mechanisms are not well understood, they appear to involve the differential recruitment of a hierarchy of generic chromatin modifying complexes and DNA methyltransferases to specific loci by RNAs during differentiation and development. A significant fraction of the genome-wide transcription of non-protein coding RNAs may be involved in this process, comprising a previously hidden layer of intermediary genetic information that (...) underpins developmental ontogeny and the differences between species, ecotypes and individuals. It is also evident that RNA editing is a primary means by which hardwired genetic information in animals can be altered by environmental signals, especially in the brain, indicating a dynamic RNA-mediated interplay between the transcriptome, the environment and the epigenome. Moreover, RNA-directed regulatory processes may also transfer epigenetic information not only within cells but also between cells and organ systems, as well as across generations. (shrink)

Genetic variability is considered a key to the evolvability of species. The conversion of an adenosine (A) to inosine (I) in primary RNA transcripts can result in an amino acid change in the encoded protein, a change in secondary structure of the RNA, creation or destruction of a splice consensus site, or otherwise alter RNA fate. Substantial transcriptome and proteome variability is generated by A‐to‐I RNA editing through site‐selective post‐transcriptional recoding of single nucleotides. We posit that this epigenetic source of (...) phenotypic variation is an unrecognized mechanism of adaptive evolution. The genetic variation introduced through editing occurs at low evolutionary cost since predominant production of the wild‐type protein is retained. This property even allows exploration of sequence space that is inaccessible through mutation, leading to increased phenotypic plasticity and provides an evolutionary advantage for acclimatization as well as long‐term adaptation. Furthermore, continuous probing for novel RNA editing sites throughout the transcriptome is an intrinsic property of the editing machinery and represents the molecular basis for increased adaptability. We propose that higher organisms have therefore evolved to systems with increasing RNA editing activity and, as a result, to more complex systems. (shrink)

Inflammatory responses are essential for the clearance of pathogens and the repair of injured tissues; however, if these responses are not properly controlled chronic inflammation can occur. Chronic inflammation is now recognized as a contributing factor to many age‐associated diseases including metabolic disorders, arthritis, neurodegeneration, and cardiovascular disease. Due to the connection between chronic inflammation and these diseases, it is essential to understand underlying mechanisms behind this process. In this review, factors that contribute to chronic inflammation are discussed. Further, we (...) emphasize the emerging roles of microRNAs (miRNAs) and other noncoding RNAs (ncRNA) in regulating chronic inflammatory states, making them important future diagnostic markers and therapeutic targets. Copyright Line: © 2015 The Authors BioEssays Published by Wiley‐VCH Verlag GmbH & Co. KGaA. (shrink)

The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Feng et al. now report a new function for UPF1—it is an E3 ubiquitin ligase that specifically promotes the decay of a key pro-muscle transcription factor: MYOD. UPF1 achieves this through its RING-like domain, which confers ubiquitin E3 ligase activity. Feng et al. provide evidence that the ability of UPF1 to destabilize MYOD represses myogenesis. In the future, it will be important to define (...) other protein substrates of UPF1-driven ubiquitination and to determine whether this biochemical activity is responsible for some of UPF1's previously defined biological functions, including in development and stress responses. The exciting findings presented by Feng et al. open up the possibility that protein turnover and RNA turnover are coupled processes. The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Here we discuss a new role for UPF1—it is directly involved in protein decay. This hidden talent raises the possibility that protein turnover and RNA turnover are coupled processes. (shrink)

All the conserved detailed results of evolution stored in DNA must be read, transcribed, and translated via an RNAmediated process. This is required for the development and growth of each individual cell. Thus, all known living organisms fundamentally depend on these RNA-mediated processes. In most cases, they are interconnected with other RNAs and their associated protein complexes and function in a strictly coordinated hierarchy of temporal and spatial steps (i.e., an RNA network). Clearly, all cellular life as we know it (...) could not function without these key agents of DNA replication, namely rRNA, tRNA, and mRNA. Thus, any definition of life that lacks RNA functions and their networks misses an essential requirement for RNA agents that inherently regulate and coordinate (communicate to) cells, tissues, organs, and organisms. The precellular evolution of RNAs occurred at the core of the emergence of cellular life and the question remained of how both precellular and cellular levels are interconnected historically and functionally. RNA-networks andRNA-communication can interconnect these levels.With the reemergence of virology in evolution, it became clear that communicating viruses and subviral infectious genetic parasites are bridging these two levels by invading, integrating, coadapting, exapting, and recombining constituent parts in host genomes for cellular requirements in gene regulation and coordination aims. Therefore, a 21st century understanding of life is of an inherently social process based on communicating RNA networks, in which viruses and cells continuously interact. (shrink)

Construction of the eukaryotic ribosome is a complex process in which a nascent ribosomal RNA (rRNA) emerging from RNA Polymerase I hierarchically folds into a native three‐dimensional structure. Modular assembly of individual RNA domains through interactions with ribosomal proteins and a myriad of assembly factors permit efficient disentanglement of the error‐prone RNA folding process. Following these dynamic events, long‐range tertiary interactions are orchestrated to compact rRNA. A combination of genetic, biochemical, and structural studies is now providing clues into how a (...) nascent rRNA is transformed into a functional ribosome with high precision. With this essay, we aim to draw attention to the poorly understood process of establishing correct RNA tertiary contacts during ribosome formation. (shrink)

The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Feng et al. now report a new function for UPF1—it is an E3 ubiquitin ligase that specifically promotes the decay of a key pro-muscle transcription factor: MYOD. UPF1 achieves this through its RING-like domain, which confers ubiquitin E3 ligase activity. Feng et al. provide evidence that the ability of UPF1 to destabilize MYOD represses myogenesis. In the future, it will be important to define (...) other protein substrates of UPF1-driven ubiquitination and to determine whether this biochemical activity is responsible for some of UPF1's previously defined biological functions, including in development and stress responses. The exciting findings presented by Feng et al. open up the possibility that protein turnover and RNA turnover are coupled processes. The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Here we discuss a new role for UPF1—it is directly involved in protein decay. This hidden talent raises the possibility that protein turnover and RNA turnover are coupled processes. (shrink)

Deamination of adenosine in RNA to form inosine has wide ranging consequences on RNA function including amino acid substitution to give proteins not encoded in the genome. What determines which adenosines in an mRNA are subject to this modification reaction? The answer lies in an understanding of the mechanism and substrate recognition properties of adenosine deaminases that act on RNA (ADARs). Our recent publication of X‐ray crystal structures of the human ADAR2 deaminase domain bound to RNA editing substrates shed considerable (...) light on how the catalytic domains of these enzymes bind RNA and promote adenosine deamination. Here we review in detail the deaminase domain‐RNA contact surfaces and present models of how full length ADARs, bearing double stranded RNA‐binding domains (dsRBDs) and deaminase domains, could process naturally occurring substrate RNAs. (shrink)

RNA editing is a major post-transcriptional mechanism that changes specific nucleotides at the RNA level. The most common RNA editing type in humans is adenosine to inosine editing, which is mediated by ADAR enzymes. RNA editing events can not only change amino acids in proteins, but also affect the functions of non-coding RNAs such as miRNAs. Recent studies have characterized thousands of miRNA RNA editing events across different cancer types. Importantly, individual cases of miRNA editing have been reported to play (...) a role in cancer development. In this review, we summarize the current knowledge of miRNA editing in cancer, and discuss the mechanisms on how miRNA-related editing events modulate the initiation and progression of human cancer. Finally, we discuss the challenges and future directions of studying miRNA editing in cancer. RNA editing is introduced by ADAR or APOBEC enzymes, leading to specific nucleotide changes, respectively. The interplays between RNA editing and miRNAs may play important roles in cancer. This graphical abstract shows four major mechanisms through which miRNAs interact with RNA editing to confer a functional impact on tumor development. (shrink)

BackgroundTemporal interference (TI) stimulation is a novel technique that enables the non-invasive modulation of deep brain regions. However, the implementation of this technology in humans has not been well-characterized or examined, including its safety and feasibility.ObjectiveWe aimed to examine the feasibility, safety, and blinding of using TI on human participants in this pilot study.Materials and methodsIn a randomized, single-blinded, and sham-controlled pilot study, healthy young participants were randomly divided into four groups [TI and transcranial alternating current stimulation (tACS) targeting (...) the right frontoparietal region, TI-sham, and tACS-sham]. Each participant was asked to complete N-back (N = 1 to 3) tasks before, during, and after one session of stimulation to assess their working memory (WM). The side effects and blinding efficacy were carefully assessed. The accuracy, reaction time (RT), and inverse efficiency score (IES, reaction time/accuracy) of the N-back tasks were measured.ResultsNo severe side effects were reported. Only mild-to-moderate side effects were observed in those who received TI, which was similar to those observed in participants receiving tACS. The blinding efficacy was excellent, and there was no correlation between the severity of the reported side effects and the predicted type of stimulation that the participants received. WM appeared to be only marginally improved by TI compared to tACS-sham, and this improvement was only observed under high-load cognitive tasks. WM seemed to have improved a little in the TI-sham group. However, it was not observed significant differences between TI and TI-sham or TI and tACS in all N-back tests.ConclusionOur pilot study suggests that TI is a promising technique that can be safely implemented in human participants. Studies are warranted to confirm the findings of this study and to further examine the effects of TI-sham stimulation as well as the effects of TI on deeper brain regions. (shrink)

Transfer RNAs (tRNAs) represent the most abundant class of RNA molecules in the cell and are key players during protein synthesis and cellular homeostasis. Aberrations in the extensive tRNA biogenesis pathways lead to severe neurological disorders in humans. Mutations in the tRNA splicing endonuclease (TSEN) and its associated RNA kinase cleavage factor polyribonucleotide kinase subunit 1 (CLP1) cause pontocerebellar hypoplasia (PCH), a heterogeneous group of neurodegenerative disorders, that manifest as underdevelopment of specific brain regions typically accompanied by microcephaly, profound motor (...) impairments, and child mortality. Recently, we demonstrated that mutations leading to specific PCH subtypes destabilize TSEN in vitro and cause imbalances of immature to mature tRNA ratios in patient‐derived cells. However, how tRNA processing defects translate to disease on a systems level has not been understood. Recent findings suggested that other cellular processes may be affected by mutations in TSEN/CLP1 and obscure the molecular mechanisms of PCH emergence. Here, we review PCH disease models linked to the TSEN/CLP1 machinery and discuss future directions to study neuropathogenesis. (shrink)

The human genome project's lasting legacies are the emerging insights into human physiology and disease, and the ascendance of biology as the dominant science of the 21st century. Sequencing revealed that >90% of the human genome is not coding for proteins, as originally thought, but rather is overwhelmingly transcribed into non‐protein coding, or non‐coding, RNAs (ncRNAs). This discovery initially led to the hypothesis that most genomic DNA is “junk”, a term still championed by some geneticists and evolutionary biologists. In contrast, (...) molecular biologists and biochemists studying the vast number of transcripts produced from most of this genome “junk” often surmise that these ncRNAs have biological significance. What gives? This essay contrasts the two opposing, extant viewpoints, aiming to explain their bases, which arise from distinct reference frames of the underlying scientific disciplines. Finally, it aims to reconcile these divergent mindsets in hopes of stimulating synergy between scientific fields. (shrink)

The advent of deep sequencing technology has unexpectedly advanced our structural understanding of molecules composed of nucleic acids. A significant amount of progress has been made recently extrapolating the chemical methods to probe RNA structure into sequencing methods. Herein we review some of the canonical methods to analyze RNA structure, and then we outline how these have been used to probe the structure of many RNAs in parallel. The key is the transformation of structural biology problems into sequencing problems, whereby (...) sequencing power can be interpreted to understand nucleic acid proximity, nucleic acid conformation, or nucleic acid‐protein interactions. Utilizing such technologies in this way has the promise to provide novel structural insights into the mechanisms that control normal cellular physiology and provide insight into how structure could be perturbed in disease. (shrink)

RNA processing in Escherichia coli and some of its phages is reviewed here, with primary emphasis on rRNA and tRNA processing. Three enzymes, RNase III, RNase E and RNase P are responsible for most of the primary endonucleolytic RNA processing events. The first two are proteins, while RNase P is a ribozyme. These three enzymes have unique functions and in their absence, the cleavage events they catalyze are not performed. On the other hand a relatively large number of exonucleases participate (...) in the trimming of the 3′ ends of tRNA precursor molecules and they can substitute for each other. Primary processing is the first event that happens to the nascent RNA molecule, while in secondary RNA processing, the substrate is a product of a primary processing event. Although most RNA processing occurs in RNP particles, it seems that only in secondary RNA processing is the RNP particle required for the reaction. Bacteria and especially bacteriophages contain self‐splicing introns which in cases were probably acquired from other species. (shrink)

RNA editing is a newly described genetic phenomenon. It encompasses widely different molecular mechanisms and events. According to the specific RNA modification, RNA editing can be broadly classified into six major types. Type II RNA editing occurs in plants and mammals; it consists predominantly in cytidine to uridine conversions resulting from deamination/transamination or transglycosylation, although in plants other mechanisms have not been excluded. Apolipoprotein B mRNA editing is the only well‐documented editing phenomenon in mammals. It is an intranuclear event that (...) occurs posttranscriptionally, coincident with splicing and polyadenylation. Recent observations indicate that the tissue‐ and sequence‐specific process is mediated by an enzyme that has separate domains for editing and sequence recognition. The presence of apolipoprotein B mRNA editing activity in tissues that do not produce the protein suggests that other RNAs may be edited and RNA editing may be a genetic phenomenon of general biological importance to the cell. (shrink)