In recent years, sequencing technologies have enabled the identification of a wide range of non-coding RNAs (ncRNAs). Unfortunately, annotation and integration of ncRNA data has lagged behind their identification. Given the large quantity of information being obtained in this area, there emerges an urgent need to integrate what is being discovered by a broad range of relevant communities. To this end, the Non-Coding RNA Ontology (NCRO) is being developed to provide a systematically structured and precisely defined controlled (...) vocabulary for the domain of ncRNAs, thereby facilitating the discovery, curation, analysis, exchange, and reasoning of data about structures of ncRNAs, their molecular and cellular functions, and their impacts upon phenotypes. The goal of NCRO is to serve as a common resource for annotations of diverse research in a way that will significantly enhance integrative and comparative analysis of the myriad resources currently housed in disparate sources. It is our belief that the NCRO ontology can perform an important role in the comprehensive unification of ncRNA biology and, indeed, fill a critical gap in both the Open Biological and Biomedical Ontologies (OBO) Library and the National Center for Biomedical Ontology (NCBO) BioPortal. Our initial focus is on the ontological representation of small regulatory ncRNAs, which we see as the first step in providing a resource for the annotation of data about all forms of ncRNAs. The NCRO ontology is free and open to all users. (shrink)

Common themes are emerging in the molecular mechanisms of long non‐coding RNA‐mediated gene repression. Long non‐coding RNAs (lncRNAs) participate in targeted gene silencing through chromatin remodelling, nuclear reorganisation, formation of a silencing domain and precise control over the entry of genes into silent compartments. The similarities suggest that these are fundamental processes of transcription regulation governed by lncRNAs. These findings have paved the way for analogous investigations on other lncRNAs and chromatin remodelling enzymes. Here we discuss these (...) common mechanisms and provide our view on other molecules that warrant similar investigations. We also present our concepts on the possible mechanisms that may facilitate the exit of genes from the silencing domains and their potential therapeutic applications. Finally, we point to future areas of research and put forward our recommendations for improvements in resources and applications of existing technologies towards targeted outcomes in this active area of research. (shrink)

New DNA sequencing technologies have provided novel insights into eukaryotic genomes, epigenomes, and the transcriptome, including the identification of new non‐coding RNA (ncRNA) classes such as promoter‐associated RNAs and long RNAs. Moreover, it is now clear that up to 90% of eukaryotic genomes are transcribed, generating an extraordinary range of RNAs with no coding capacity. Taken together, these new discoveries are modifying the status quo in genomic science by demonstrating that the eukaryotic gene pool is (...) divided into two distinct categories of transcripts: protein‐coding and non‐coding. The function of the majority of ncRNAs produced by the transcriptome is largely unknown; however, it is probable that many are associated with epigenetic mechanisms. The purpose of this review is to describe the most recent discoveries in the ncRNA field that implicate these molecules as key players in the epigenome. (shrink)

Altered cellular metabolism is an emerging hallmark of cancer. Accumulating recent evidence links long non‐coding RNAs (lncRNAs), a still poorly understood class of non‐coding RNAs, to cancer metabolism. Here we review the emerging findings on the functions of lncRNAs in cancer metabolism, with particular emphasis on how lncRNAs regulate glucose and glutamine metabolism in cancer cells, discuss how lncRNAs regulate various aspects of cancer metabolism through their cross‐talk with other macromolecules, explore the mechanistic conceptual framework of (...) lncRNAs in reprogramming metabolism in cancers, and highlight the challenges in this field. A more in‐depth understanding of lncRNAs in cancer metabolism may enable the development of novel and effective therapeutic strategies targeting cancer metabolism. (shrink)

Altered cellular metabolism is an emerging hallmark of cancer. Accumulating recent evidence links long non‐coding RNAs (lncRNAs), a still poorly understood class of non‐coding RNAs, to cancer metabolism. Here we review the emerging findings on the functions of lncRNAs in cancer metabolism, with particular emphasis on how lncRNAs regulate glucose and glutamine metabolism in cancer cells, discuss how lncRNAs regulate various aspects of cancer metabolism through their cross‐talk with other macromolecules, explore the mechanistic conceptual framework of (...) lncRNAs in reprogramming metabolism in cancers, and highlight the challenges in this field. A more in‐depth understanding of lncRNAs in cancer metabolism may enable the development of novel and effective therapeutic strategies targeting cancer metabolism. (shrink)

Over the past decade, high‐throughput studies have identified many novel transcripts. While their existence is undisputed, their coding potential and functionality have remained controversial. Recent computational approaches guided by ribosome profiling have indicated that translation is far more pervasive than anticipated and takes place on many transcripts previously assumed to be non‐coding. Some of these newly discovered translated transcripts encode short, functional proteins that had been missed in prior screens. Other transcripts are translated, but it might be the (...) process of translation rather than the resulting peptides that serves a function. Here, we review annotation studies in zebrafish to discuss the challenges of placing RNAs onto the continuum that ranges from functional protein‐encoding mRNAs to potentially non‐functional peptide‐producing RNAs to non‐coding RNAs. As highlighted by the discovery of the novel signaling peptide Apela/ELABELA/Toddler, accurate annotations can give rise to exciting opportunities to identify the functions of previously uncharacterized transcripts. (shrink)

Kawasaki disease (KD) is an acute self‐limiting vasculitis with coronary complications, usually occurring in children. The incidence of KD in children is increasing year by year, mainly in East Asian countries, but relatively stably in Europe and America. Although studies on KD have been reported, the pathogenesis of KD is unknown. With the development of high‐throughput sequencing technology, growing number of regulatory noncoding RNAs (ncRNAs) including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA) have been identified to (...) involved in KD. However, the role of ncRNAs in KD has not been comprehensively elucidated. Therefore, it is significative to study the regulatory role of ncRNA in KD, which might help to uncover new and effective therapeutic strategies for KD. In this review, we summarize recent studies on ncRNA in KD from the perspectives of immune disorders, inflammatory disorders, and endothelial dysfunction, and highlight the potential of ncRNAs as therapeutic targets for KD. (shrink)

Identification of non-coding RNAs (ncRNAs) has been significantly improved over the past decade. On the other hand, semantic annotation of ncRNA data is facing critical challenges due to the lack of a comprehensive ontology to serve as common data elements and data exchange standards in the field. We developed the Non-Coding RNA Ontology (NCRO) to handle this situation. By providing a formally defined ncRNA controlled vocabulary, the NCRO aims to fill a specific and highly needed niche in (...) semantic annotation of large amounts of ncRNA biological and clinical data. (shrink)

Identification of non-coding RNAs (ncRNAs) has been significantly enhanced due to the rapid advancement in sequencing technologies. On the other hand, semantic annotation of ncRNA data lag behind their identification, and there is a great need to effectively integrate discovery from relevant communities. To this end, the Non-Coding RNA Ontology (NCRO) is being developed to provide a precisely defined ncRNA controlled vocabulary, which can fill a specific and highly needed niche in unification of ncRNA biology.

Long non‐coding RNAs (lncRNAs) have recently gained increasing attention because of their crucial roles in gene regulatory processes. Functional studies using mammalian skin as a model system have revealed their role in controlling normal tissue homeostasis as well as the transition to a diseased state. Here, we describe how lncRNAs regulate differentiation to preserve an undifferentiated epidermal progenitor compartment, and to maintain a functional skin permeability barrier. Furthermore, we will reflect on recent work analyzing the impact of lncRNAs (...) on the progression from normal epithelium to the development of skin disorders and cancer. (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)

Recent experimental evidence suggests that most of the genome is transcribed into non‐coding RNAs. The initial transcripts undergo further processing generating shorter, metabolically stable RNAs with diverse functions. Small nucleolar RNAs (snoRNAs) are non‐coding RNAs that modify rRNAs, tRNAs, and snRNAs that were considered stable. We review evidence that snoRNAs undergo further processing. High‐throughput sequencing and RNase protection experiments showed widespread expression of snoRNA fragments, known as snoRNA‐derived RNAs (sdRNAs). Some sdRNAs resemble miRNAs, (...) these can associate with argonaute proteins and influence translation. Other sdRNAs are longer, form complexes with hnRNPs and influence gene expression. C/D box snoRNA fragmentation patterns are conserved across multiple cell types, suggesting a processing event, rather than degradation. The loss of expression from genetic loci that generate canonical snoRNAs and processed snoRNAs results in diseases, such as Prader‐Willi Syndrome, indicating possible physiological roles for processed snoRNAs. We propose that processed snoRNAs acquire new roles in gene expression and represent a new class of regulatory RNAs distinct from canonical snoRNAs.Also watch the Video Abstract. (shrink)

The H19 gene produces a non‐coding RNA, which is abundantly expressed during embryonic development and down‐regulated after birth. Although this gene was discovered over 20 years ago, its function has remained unclear. Only recently a role was identified for the non‐coding RNA and/or its microRNA partner, first as a tumour suppressor gene in mice, then as a trans‐regulator of a group of co‐expressed genes belonging to the imprinted gene network that is likely to control foetal and early postnatal (...) growth in mice. The mechanisms underlying this transcriptional or post‐transcriptional regulation remain to be discovered, perhaps by identifying the protein partners of the full‐length H19 RNA or the targets of the microRNA. This first in vivo evidence of a functional role for the H19 locus provides new insights into how genomic imprinting helps to control embryonic growth. (shrink)

The largest transcriptome reported so far comprises 60,770 mouse full‐length cDNA clones, and is an effective reference data set for comparative transcriptomics. The number of mouse cDNAs identified greatly exceeds the number of genes predicted from the sequenced human and mouse genomes. This is largely because of extensive alternative splicing and the presence of many non‐coding RNAs (ncRNAs), which are difficult to predict from genomic sequences. Notably, ncRNAs are a major component of the transcriptomes of higher organisms, and (...) many sense–antisense pairs have been identified. The ncRNAs function in a range of regulatory mechanisms for gene expression and other biological processes. They might also have contributed to the increased functional diversification of genomes during evolution. In this review, we discuss aspects of the transcriptome of various organisms in relation to the mouse data, in order to shed light on the regulatory mechanisms and physiological significance of these abundant RNAs. BioEssays 26:833–843, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The central dogma of biology holds that genetic information normally flows from DNA to RNA to protein. As a consequence it has been generally assumed that genes generally code for proteins, and that proteins fulfil not only most structural and catalytic but also most regulatory functions, in all cells, from microbes to mammals. However, the latter may not be the case in complex organisms. A number of startling observations about the extent of non-protein-coding RNA (ncRNA) transcription in the higher (...) eukaryotes and the range of genetic and epigenetic phenomena that are RNA-directed suggests that the traditional view of the structure of genetic regulatory systems in animals and plants may be incorrect. ncRNA dominates the genomic output of the higher organisms and has been shown to control chromosome architecture, mRNA turnover and the developmental timing of protein expression, and may also regulate transcription and alternative splicing. This paper re-examines the available evidence and suggests a new framework for considering and understanding the genomic programming of biological complexity, autopoletic development and phenotypic variation. BioEssays 25:930-939,2003. (C) 2003 Wiley Periodicals, Inc. (shrink)

Approaches to induce tumor differentiation often result in manageable and therapy‐naïve cellular states in cancer cells. This transformation is achieved by activating pathways that drive tumor cells away from plasticity, a state that commonly correlates with enhanced aggression, metastasis and resistance to therapy. Here, we discuss signaling pathways, epigenetics and non‐coding RNAs as three main regulatory levels with the potential to drive tumor differentiation and hence as potential targets in differentiation therapy approaches. The success of an effective therapeutic (...) regimen in one cancer, however, does not necessarily sustain across cancer types; a phenomenon largely resulting from heterogeneity in the genetic and physiological landscapes of tumor types necessitating an approach designed for each cancer's unique genetic and phenotypic build‐up. (shrink)

RNA polymerase II (RNAP II) non‐coding transcription is now known to cover almost the entire eukaryotic genome, a phenomenon referred to as pervasive transcription. As a consequence, regions previously thought to be non‐transcribed are subject to the passage of RNAP II and its associated proteins for histone modification. This is the case for the nucleosome‐depleted regions (NDRs), which provide key sites of entry into the chromatin for proteins required for the initiation of coding gene transcription and DNA replication. (...) In this review, recent data on the effects of pervasive transcription through NDRs are summarized and a model is proposed to explain how RNAP II‐driven transcription is able to modify the nucleosomes flanking the NDRs, leading to nucleosome repositioning and NDR closure. Even though much of the mechanistic detail underlying these events remains to be elucidated, such a model provides a basis to explain how non‐coding transcription through NDRs can regulate the initiation of coding gene expression and DNA replication. (shrink)

There are two intriguing paradoxes in molecular biology-the inconsistent relationship between organismal complexity and (1) cellular DNA content and (2) the number of protein-coding genes-referred to as the C-value and G-value paradoxes, respectively. The C-value paradox may be largely explained by varying ploidy. The G-value paradox is more problematic, as the extent of protein coding sequence remains relatively static over a wide range of developmental complexity. We show by analysis of sequenced genomes that the relative amount of non-protein- (...) class='Hi'>coding sequence increases consistently with complexity. We also show that the distribution of introns in complex organisms is non-random. Genes composed of large amounts of intronic sequence are significantly overrepresented amongst genes that are highly expressed in the nervous system, and amongst genes downregulated in embryonic stem cells and cancers. We suggest that the informational paradox in complex organisms may be explained by the expansion of cis-acting regulatory elements and genes specifying trans-acting non-protein-coding RNAs. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Reviewed by:Women Philosophers: Genre and the Boundaries of PhilosophyLorraine CodeCatherine Villanueva Gardner. Women Philosophers: Genre and the Boundaries of Philosophy. Boulder, CO: Westview, 2003. Pp. xv + 198. Paper, $22.00.In a tradition which "trains us to read purely for content" (xii), Catherine Gardner wonders how to read the philosophy of five women who write in "non-standard philosophical forms" (xiii): Mechthild of Magdeburg's poetry, Christine de Pisan's allegory, Catharine Macaulay's (...) epistolary form, and Mary Wollstonecraft's and George Eliot's fiction. Asking how these authors' gender and their works' genre bear on their exclusion from canonical philosophy with its reliance on rigorous argument unsullied by stylistic considerations, she argues that form is integral to understanding philosophy, and can impede its recognition as philosophy. Specifically, she wonders what these historical writings can offer present-day feminist ethics?Gardner's readings and her thesis about style and genre as conditions of philosophical legitimacy are provocative. She urges "reading past" forms deemed inhospitable to moral truth—such as Macaulay's epistolary style (44-45)—to encounter the author as moral philosopher, and explain her invisibility as such. Eliot's philosophy "demands the form of a novel" (123), she proposes, and Wollstonecraft's principles of style "are ultimately principles of morality as well" (92). More complex is the poetically articulated moral epistemology in Mechthild's The Flowing Light, with God, speaking through Mechthild, as its author (154-56). Because these forms—epistolary, allegorical, mystical-poetic, fictional—have been most accessible to women, Gardner urges feminists to consider how these authors' gender bears on their exclusion from moral philosophy. Owing to women's "greater capacity for emotion and... weaker capacity for reason" (155), mystics such as Mechthild were deemed well-suited to write as they did; yet works attributed to God stand immune to philosophical argument. Macaulay's thoughts on government and social reform were judged secondary to her "feminine" ones about educating women for marriage and domesticity (26-27). Gardner is persuaded and persuasive about the philosophical stature of the works she discusses. Yet if a thinker's gender denies her philosophical status, how can she bypass those exclusionary structures—even if, like Eliot, she chooses a male name? If a work's genre removes it from the sustained argumentative debate that is the hallmark of western philosophy, how can it claim a place there?There are no easy answers, but the questions spark numerous others. Perplexing is Gardner's contention that these women are ignored because they defy norms of style and method. But how would she classify Plato's dialogues, Voltaire's Candide, Pascal's and Nietzsche's aphorisms, Wittgenstein's numbered propositions,or Sartre's, Camus' (and Beauvoir's) philosophical novels, given their maverick styles? Style alone cannot effect or explain the exclusions she deplores. More puzzling are Gardner's conceptions of standard method and dominant form (e.g., 24, 120, 175), since she does not elaborate, apart from indicating that both require rigorous prose argument. But formal and methodological orthodoxy varies historically, as in the influence of scholasticism, for Christine, which receives no mention, or Gardner's ahistorical suggestion that the absence of a "normative subject as an independent, autonomous individual" (171) is a lacuna in Mechthild's work. Why would a thirteenth-century writer presuppose an Enlightenment subject? These issues demand attention in a work of historical scholarship.A different question troubles the method discussion. The author regrets certain women's exclusion from the canon despite the philosophical nature of their work, maintaining that [End Page 215] works whose styles/forms diverge from the standard count, nonetheless, as philosophy. These women demonstrate that philosophy need not be couched in formal argument: poetry, allegory, novels can also articulate philosophical theories. But—if my reading is correct—here Gardner is inconsistent. She commends the philosophy in Macaulay's Letters, claiming it "can and does contain the sort of sustained argument... uncontroversially identifiable as... philosophical" (44), and makes similar claims for Wollstonecraft and Eliot. But in legitimating these works by received standards of argument after all, Gardner weakens the force of her claims that philosophy—good philosophy—need not be presented in orthodox form, thus... (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)

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)

A relatively late arrival on the philosophical scene, feminist epistemology has evolved and undergone multiple refinements since, in 1981, I posed the then still outrageous question: “is the sex of the knower epistemologically significant?” At the time, that question was beginning to receive affirmative answers, within philosophy, from the essays in Sandra Harding and Merrill Hintikka's Discovering Reality: Feminist Perspectives on Epistemology, Metaphysics, Methodology, and Philosophy of Science, from Nancy Hartsock's Money, Sex, and Power: Toward a Feminist Historical Materialism, and (...) from Alison Jaggar's Feminist Politics and Human Nature, with its chapter on feminist epistemology, all published in 1983. These writings were mapping a new epistemic terrain within professional philosophy that was also being opened out in the work of such non‐philosophers as Dorothy Smith, Carol Gilligan, and Nancy Chodorow. Nonetheless, in the philosophical projects of the late 1960s and throughout the 1970s, even as feminist moral and political philosophy were growing to constitute an impressive body of critical‐constructive literature, the suggestion that analogous interventions were not merely indicated, but urgently required, in epistemology, philosophy of science, and even logic still sounded like a preposterous manifestation of ideological excess. Knowledge, science, and logic seemed, virtually by definition, to stand secure as the repositories and guardians of truth and objectivity, occupants of a space isolated and protected from the vagaries of politics and of gendered specificities. (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)

Most molecular biological concepts derive from physical chemical assumptions about the genetic code that are basically more than 40 years old. Additionally, systems biology, another quantitative approach, investigates the sum of interrelations to obtain a more holistic picture of nucleotide sequence order. Recent empirical data on genetic code compositions and rearrangements by mobile genetic elements and non-coding RNAs, together with results of virus research and their role in evolution, does not really fit into these concepts and compel a (...) re-examination. In this review we try to find an alternate hypothesis. It seems plausible now that if we look at the abundance of regulatory RNAs and persistent viruses in host genomes, we will find more and more evidence that the key players that edit the genetic codes of host genomes are consortia of RNA agents and viruses that drive evolutionary novelty and regulation of cellular processes in all steps of development. This agent-based approach may lead to a qualitative RNA sociology that investigates and identifies relevant behavioural motifs of cooperative RNA consortia. In addition to molecular biological perspectives this may lead to a better understanding of genetic code evolution and dynamics. (shrink)

Human telomerase progressively emerged as a multifaceted ribonucleoprotein complex with additional functions beyond telomeric repeat synthesis. Both the hTERT catalytic subunit and the hTR long non‐coding RNA (lncRNA) subunit are engaged in highly regulated cellular pathways that, together, contribute to cell fitness and protection against apoptosis. We recently described a new role for hTR in regulating the abundance of replication protein A at telomeres, adding to the growing repertoire of hTR’s functions. Here, we focus on the non‐canonical roles of (...) hTR and discuss them in the context of the structural elements of the lncRNA. We propose that some functions of hTR may compete amongst each other through distinct interactions with its partners, proteins or mRNAs. We postulate that hTR’s non‐canonical functions may be highly relevant in the context of normal somatic cells that naturally silence hTERT gene, while keeping hTR expression. (shrink)

Modern cells present no signs of a putative prebiotic RNA world. However, RNA coding is not a sine qua non for the accumulation of catalytic polypeptides. Thus, cellular proteins spontaneously fold into active structures that are resistant to proteolysis. The law of mass action suggests that binding domains are stabilized by specific interactions with their substrates. Random polypeptide synthesis in a prebiotic world has the potential to initially produce only a very small fraction of polypeptides that can fold spontaneously (...) into catalytic domains. However, that fraction can be enriched by proteolytic activities that destroy the unfolded polypeptides and regenerate amino acids that can be recycled into polypeptides. In this open system scenario the stable domains that accumulate and the chemical environment in which they are accumulated are linked through self coding of polypeptide structure. Such open polypeptide systems may have been the precursors to the cellular ribonucleoprotein (RNP) world that evolved subsequently. (shrink)

Phenotypic divergence among animal species may be due in part to species‐specific (SS) regulation of gene expression by small, non‐coding regulatory RNAs termed “microRNAs”. This phenomenon can be modulated by several variables. First, microRNA genes vary by their level of conservation, many of them being SS, or unique to a particular evolutionary lineage. Second, microRNA expression levels vary spatially and temporally in different species. Lastly, while microRNAs bind the 3′UTR of target genes in order to silence their expression, (...) the binding sites themselves are often non‐conserved. The variability of the miRNA‐target paradigm between different species is thus multifactorial, and this paradigm has only just started to gain attention from researchers in various fields. Here we present and discuss recent findings regarding the characteristics and implications of SS microRNA regulation. (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)

Research has indicated that microRNAs (miRNAs), a special class of non-coding RNAs (ncRNAs), can perform important roles in different biological and pathological processes. miRNAs’ functions are realized by regulating their respective target genes (targets). It is thus critical to identify and analyze miRNA-target interactions for a better understanding and delineation of miRNAs’ functions. However, conventional knowledge discovery and acquisition methods have many limitations. Fortunately, semantic technologies that are based on domain ontologies can render great assistance in this regard. (...) In our previous investigations, we developed a miRNA domain-specific application ontology, Ontology for MIcroRNA Target (OMIT), to provide the community with common data elements and data exchange standards in the miRNA research. This paper describes (1) our continuing efforts in the OMIT ontology development and (2) the application of the OMIT to enable a semantic approach for knowledge capture of miRNA-target interactions. (shrink)

The genetic code has evolved from its initial non-degenerate wobble version until reaching its present state of degeneracy. By using the stereochemical hypothesis, we revisit the problem of codon assignations to the synonymy classes of amino-acids. We obtain these classes with a simple classifier based on physico-chemical properties of nucleic bases, like hydrophobicity and molecular weight. Then we propose simple RNA ring structures that present, overlap included, one and only one codon by synonymy class as solutions of a combinatory variational (...) problem. We compare these solutions to sequences of present RNAs considered as relics, with a high interspecific invariance, like invariant parts of tRNAs and micro-RNAs. We conclude by emphasizing some optimal properties of the genetic code. (shrink)

The landscapes of mammalian genomes are characterized by complex patterns of intersecting and overlapping sense and antisense transcription, giving rise to large numbers of coding and non‐protein‐coding RNAs (ncRNAs). A recent report by Kapranov and colleagues1 describes three potentially novel classes of RNAs located at the very edges of protein‐coding genes. The presence of RNAs from one of these classes appears to be correlated with the expression levels of their associated genes. These results suggest (...) that a proportion of these RNAs might have roles in the cis‐regulation of neighbouring protein‐coding genes' expression. BioEssays 29:1077–1080, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Thomas Kuhn described the progress of science as comprising occasional paradigm shifts separated by interludes of ‘normal science’. The paradigm that has held sway since the inception of molecular biology is that genes (mainly) encode proteins. In parallel, theoreticians posited that mutation is random, inferred that most of the genome in complex organisms is non‐functional, and asserted that somatic information is not communicated to the germline. However, many anomalies appeared, particularly in plants and animals: the strange genetic phenomena of paramutation (...) and transvection; introns; repetitive sequences; a complex epigenome; lack of scaling of (protein‐coding) genes and increase in ‘noncoding’ sequences with developmental complexity; genetic loci termed ‘enhancers’ that control spatiotemporal gene expression patterns during development; and a plethora of ‘intergenic’, overlapping, antisense and intronic transcripts. These observations suggest that the original conception of genetic information was deficient and that most genes in complex organisms specify regulatory RNAs, some of which convey intergenerational information. Also see the video abstract here: https://youtu.be/qxeGwahBANw. (shrink)

Recent studies indicate that mammalian chromosomes contain discrete cis‐acting loci that control replication timing, mitotic condensation, and stability of entire chromosomes. Disruption of the large non‐coding RNA gene ASAR6 results in late replication, an under‐condensed appearance during mitosis, and structural instability of human chromosome 6. Similarly, disruption of the mouse Xist gene in adult somatic cells results in a late replication and instability phenotype on the X chromosome. ASAR6 shares many characteristics with Xist, including random mono‐allelic expression and asynchronous (...) replication timing. Additional “chromosome engineering” studies indicate that certain chromosome rearrangements affecting many different chromosomes display this abnormal replication and instability phenotype. These observations suggest that all mammalian chromosomes contain “inactivation/stability centers” that control proper replication, condensation, and stability of individual chromosomes. Therefore, mammalian chromosomes contain four types of cis‐acting elements, origins, telomeres, centromeres, and “inactivation/stability centers”, all functioning to ensure proper replication, condensation, segregation, and stability of individual chromosomes. (shrink)

RNA's role in genome rearrangement. Ciliated protists, such as Oxytricha, shown, have two types of nuclei that differentiate from each other. Development in these microbial eukaryotes provides a paragon for studies of genome remodeling, with extensive use of non‐coding RNAs. On pages 84–87 of this issue, Wenwen Fang and Laura Landweber discuss how RNA‐guided processes of genome rearrangement or repair could influence other eukaryotes. Cover by Wenyi Fang. SEM images courtesy of Robert Hammersmith.

RNA's role in genome rearrangement. Ciliated protists, such as Oxytricha, shown, have two types of nuclei that differentiate from each other. Development in these microbial eukaryotes provides a paragon for studies of genome remodeling, with extensive use of non‐coding RNAs. On pages 84–87 of this issue, Wenwen Fang and Laura Landweber discuss how RNA‐guided processes of genome rearrangement or repair could influence other eukaryotes. Cover by Wenyi Fang. SEM images courtesy of Robert Hammersmith.

Over the last decades, it has become evident that highly complex networks of regulators govern post‐transcriptional regulation of gene expression. A novel class of Argonaute (Ago)‐associated RNA molecules, the agotrons, was recently shown to function in a Drosha‐ and Dicer‐independent manner, hence bypassing the maturation steps required for canonical microRNA (miRNA) biogenesis. Agotrons are found in most mammals and associate with Ago as ∼100 nucleotide (nt) long RNA species. Here, we speculate on the functional and biological relevance of agotrons: (i) (...) agotrons could serve as non‐promiscuous miRNA‐like regulators with reduced off‐targeting or (ii) agotrons could encompass other putative functions, such as protecting Ago proteins from taking up aberrant short RNAs or by rescuing and stabilizing otherwise unloaded Ago‐proteins from degradation. Collectively, agotrons have emerged as a novel class of interesting non‐coding RNA molecules, but their full functional potential and biological impact still remain to be disclosed. (shrink)

Theoretical minimal RNA rings are candidate primordial genes evolved for non‐redundant coding of the genetic code's 22 coding signals (one codon per biogenic amino acid, a start and a stop codon) over the shortest possible length: 29520 22‐nucleotide‐long RNA rings solve this min‐max constraint. Numerous RNA ring properties are reminiscent of natural genes. Here we present analyses showing that all RNA rings lack dinucleotide CG (a mutable, chemically instable dinucleotide coding for Arginine), bearing a resemblance to known (...) CG‐depleted genomes. CG in “incomplete” RNA rings (not coding for all coding signals, with only 3–12 nucleotides) gradually decreases towards CG absence in complete, 22‐nucleotide‐long RNA rings. Presumably, feedback loops during RNA ring growth during evolution (when amino acid assignment fixed the genetic code) assigned Arg to codons lacking CG (AGR) to avoid CG. Hence, as a chemical property of base pairs, CG mutability restructured the genetic code, thereby establishing itself as genetically encoded biological information. (shrink)

In mice, dosage compensation of X‐linked gene expression is achieved through the inactivation of one of the two X‐chromosomes in XX female cells. The complex epigenetic process leading to X‐inactivation is largely controlled by Xist and Tsix, two non‐coding genes of opposing function. Xist RNA triggers X‐inactivation by coating the inactive X, while Tsix is critical for the designation of the active X‐chromosome through cis‐repression of Xist RNA accumulation. Recently, a plethora of trans‐acting factors and cis‐regulating elements have been (...) suggested to act as key regulators of either Xist, Tsix or both; these include ubiquitous factors such as Yy1 and Ctcf, developmental proteins such as Nanog, Oct4 and Sox2, and X‐linked regulators such as Rnf12. In this paper we summarise recent advances in our knowledge of the regulation of Xist and Tsix in embryonic stem (ES) and differentiating ES cells. (shrink)

Small non‐coding RNAs (microRNAs or miRs) represent one of the most fertile areas of cancer research and recent advances in the field have prompted us to reconsider the traditional concept of cancer. Some miRs exert negative control over the expression of numerous oncoproteins in normal cells and consequently their deregulation is believed to be an important mechanism underlying cancer development and progression. Owing to their distinct patterns of expression associated with cancer type, remarkable stability and presence in blood (...) and other body fluids, miRs are considered to be highly promising cancer biomarkers. The identification of “miR signatures” associating cancer cell phenotypes with disease outcome and specific risk factor exposures will undoubtedly open new avenues for early diagnosis and therapy of cancer, as well as for the development of novel strategies for cancer prevention. (shrink)

RNA modifications have recently emerged as an important regulatory layer of gene expression. The most prevalent and reversible modification on messenger RNA (mRNA), N6‐methyladenosine, regulates most steps of RNA metabolism and its dysregulation has been associated with numerous diseases. Other modifications such as 5‐methylcytosine and N1‐methyladenosine have also been detected on mRNA but their abundance is lower and still debated. Adenosine to inosine RNA editing is widespread on coding and non‐coding RNA and can alter mRNA decoding as well (...) as protect against autoimmune diseases. 2′‐O‐methylation of the ribose and pseudouridine are widespread on ribosomal and transfer RNA and contribute to proper RNA folding and stability. While the understanding of the individual role of RNA modifications has now reached an unprecedented stage, still little is known about their interplay in the control of gene expression. In this review we discuss the examples where such interplay has been observed and speculate that with the progress of mapping technologies more of those will rapidly accumulate. (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)

In recent years, sequencing technologies have enabled the identification of a wide range of non-coding RNAs (ncRNAs). Unfortunately, annotation and integration of ncRNA data has lagged behind their identification. Given the large quantity of information being obtained in this area, there emerges an urgent need to integrate what is being discovered by a broad range of relevant communities. To this end, the Non-Coding RNA Ontology (NCRO) is being developed to provide a systematically structured and precisely defined controlled (...) vocabulary for the domain of ncRNAs, thereby facilitating the discovery, curation, analysis, exchange, and reasoning of data about structures of ncRNAs, their molecular and cellular functions, and their impacts upon phenotypes. The goal of NCRO is to serve as a common resource for annotations of diverse research in a way that will significantly enhance integrative and comparative analysis of the myriad resources currently housed in disparate sources. It is our belief that the NCRO ontology can perform an important role in the comprehensive unification of ncRNA biology and, indeed, fill a critical gap in both the Open Biological and Biomedical Ontologies (OBO) Library and the National Center for Biomedical Ontology (NCBO) BioPortal. Our initial focus is on the ontological representation of small regulatory ncRNAs, which we see as the first step in providing a resource for the annotation of data about all forms of ncRNAs. (shrink)

Recent investigations surprisingly indicate that single RNA "stem-loops" operate solely by chemical laws that act without selective forces, and in contrast, self-ligated consortia of RNA stem-loops operate by biological selection. To understand consortial RNA selection, the concept of single quasi-species and its mutant spectra as drivers of RNA variation and evolution is rethought here. Instead, we evaluate the current RNA world scenario in which consortia of cooperating RNA stem-loops are the basic players. We thus redefine quasispecies as RNA quasispecies consortia (...) and argue that it has essential behavioral motifs that are relevant to the inherent variation, evolution and diversity in biology. We propose that qs-c is an especially innovative force. We apply qs-c thinking to RNA stem-loops and evaluate how it yields altered bulges and loops in the stem-loop regions, not as errors, but as a natural capability to generate diversity. This basic competence-not error-opens a variety of combinatorial possibilities which may alter and create new biological interactions, identities and newly emerged self identity functions. Thus RNA stem-loops typically operate as cooperative modules, like members of social groups. From such qs-c of stem-loop groups we can trace a variety of RNA secondary structures such as ribozymes, viroids, viruses, mobile genetic elements as abundant infection derived agents that provide the stem-loop societies of small and long non-coding RNAs. (shrink)

Literature on maternal exposures and the risk of epigenetic changes or diseases in the offspring is growing. Paternal contributions are often not considered. However, some animal and epidemiologic studies on various contaminants, nutrition, and lifestyle‐related conditions suggest a paternal influence on the offspring's future health. The phenotypic outcomes may have been attributed to DNA damage or mutations, but increasing evidence shows that the inheritance of environmentally induced functional changes of the genome, and related disorders, are (also) driven by epigenetic components. (...) In this essay we suggest the existence of epigenetic windows of susceptibility to environmental insults during sperm development. Changes in DNA methylation, histone modification, and non‐coding RNAs are viable mechanistic candidates for a non‐genetic transfer of paternal environmental information, from maturing germ cell to zygote. Inclusion of paternal factors in future research will ultimately improve the understanding of transgenerational epigenetic plasticity and health‐related effects in future generations. (shrink)

While heredity is predominantly controlled by what deoxyribonucleic acid (DNA) sequences are passed from parents to their offspring, a small but growing number of traits have been shown to be regulated in part by the non‐genetic inheritance of information. Transgenerational epigenetic inheritance is defined as heritable information passed from parents to their offspring without changing the DNA sequence. Work of the past seven decades has transitioned what was previously viewed as rare phenomenology, into well‐established paradigms by which numerous traits can (...) be modulated. For the most part, studies in model organisms have correlated transgenerational epigenetic inheritance phenotypes with changes in epigenetic modifications. The next steps for this field will entail transitioning from correlative studies to causal ones. Here, we delineate the major molecules that have been implicated in transgenerational epigenetic inheritance in both mammalian and non‐mammalian models, speculate on additional molecules that could be involved, and highlight some of the tools which might help transition this field from correlation to causation. (shrink)

Understanding the functional mechanisms underlying genetic signals associated with complex traits and common diseases, such as cancer, diabetes and Alzheimer's disease, is a formidable challenge. Many genetic signals discovered through genome‐wide association studies map to non‐protein coding sequences, where their molecular consequences are difficult to evaluate. This article summarizes concepts for the systematic interpretation of non‐coding genetic signals using genome annotation data sets in different cellular systems. We outline strategies for the global analysis of multiple association intervals and (...) the in‐depth molecular investigation of individual intervals. We highlight experimental techniques to validate candidate (potential causal) regulatory variants, with a focus on novel genome‐editing techniques including CRISPR/Cas9. These approaches are also applicable to low‐frequency and rare variants, which have become increasingly important in genomic studies of complex traits and diseases. There is a pressing need to translate genetic signals into biological mechanisms, leading to prognostic, diagnostic and therapeutic advances. (shrink)

Non‐coding centromeres, which dictate kinetochore formation for proper chromosome segregation, are extremely divergent in DNA sequences across species but are under active transcription carried out by RNA polymerase (RNAP) II. The RNAP II‐mediated centromeric transcription has been shown to facilitate the deposition of the centromere protein A (CENP‐A) to centromeres, establishing a conserved and critical role of centromeric transcription in centromere maintenance. Our recent work revealed another role of centromeric transcription in chromosome segregation: maintaining centromeric cohesion during mitosis. Interestingly, (...) this role appears to be fulfilled through ongoing centromeric transcription rather than centromeric transcripts. In addition, we found that centromeric transcription may not require some of the traditional transcription initiation factors, suggestive of “uniqueness” in its regulation. In this review, we discuss the novel role and regulation of centromeric transcription as well as the potential underlying mechanisms. (shrink)