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Non-coding RNAs (ncRNAs) are a heterogeneous group of transcripts that, by definition, are not translated into proteins. Since their discovery, ncRNAs have emerged as important regulators of multiple biological functions across a range of cell types and tissues, and their dysregulation has been implicated in disease. Notably, much research has focused on the link between microRNAs (miRNAs) and human cancers, although other ncRNAs, such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), are also emerging as relevant contributors to human disease. In this Review, we summarize our current understanding of the roles of miRNAs, lncRNAs and circRNAs in cancer and other major human diseases, notably cardiovascular, neurological and infectious diseases. Further, we discuss the potential use of ncRNAs as biomarkers of disease and as therapeutic targets.In this Review, the authors describe our current knowledge of the role of microRNAs, long non-coding RNAs and circular RNAs in disease, with a focus on cardiovascular, neurological, infectious diseases and cancer. Further, they discuss the potential use of non-coding RNAs as disease biomarkers and as therapeutic targets.

Genes specifying long non-coding RNAs (lncRNAs) occupy a large fraction of the genomes of complex organisms. The term ‘lncRNAs’ encompasses RNA polymerase I (Pol I), Pol II and Pol III transcribed RNAs, and RNAs from processed introns. The various functions of lncRNAs and their many isoforms and interleaved relationships with other genes make lncRNA classification and annotation difficult. Most lncRNAs evolve more rapidly than protein-coding sequences, are cell type specific and regulate many aspects of cell differentiation and development and other physiological processes. Many lncRNAs associate with chromatin-modifying complexes, are transcribed from enhancers and nucleate phase separation of nuclear condensates and domains, indicating an intimate link between lncRNA expression and the spatial control of gene expression during development. lncRNAs also have important roles in the cytoplasm and beyond, including in the regulation of translation, metabolism and signalling. lncRNAs often have a modular structure and are rich in repeats, which are increasingly being shown to be relevant to their function. In this Consensus Statement, we address the definition and nomenclature of lncRNAs and their conservation, expression, phenotypic visibility, structure and functions. We also discuss research challenges and provide recommendations to advance the understanding of the roles of lncRNAs in development, cell biology and disease.This Consensus Statement addresses the definition, nomenclature and classification of long non-coding RNAs, and provides a shared viewpoint on their features and functions. The authors also discuss research challenges and provide recommendations to advance our understanding of long non-coding RNAs.

Long non-coding RNAs (lncRNAs) outnumber protein-coding transcripts, but their functions remain largely unknown. In this Review, we discuss the emerging roles of lncRNAs in the control of gene transcription. Some of the best characterized lncRNAs have essential transcription cis-regulatory functions that cannot be easily accomplished by DNA-interacting transcription factors, such as XIST, which controls X-chromosome inactivation, or imprinted lncRNAs that direct allele-specific repression. A growing number of lncRNA transcription units, including CHASERR, PVT1 and HASTER (also known as HNF1A-AS1) act as transcription-stabilizing elements that fine-tune the activity of dosage-sensitive genes that encode transcription factors. Genetic experiments have shown that defects in such transcription stabilizers often cause severe phenotypes. Other lncRNAs, such as lincRNA-p21 (also known as Trp53cor1) and Maenli (Gm29348) contribute to local activation of gene transcription, whereas distinct lncRNAs influence gene transcription in trans. We discuss findings of lncRNAs that elicit a function through either activation of their transcription, transcript elongation and processing or the lncRNA molecule itself. We also discuss emerging evidence of lncRNA involvement in human diseases, and their potential as therapeutic targets.This Review discusses the emerging roles of long non-coding RNAs (lncRNAs) in the regulation of transcription, for example by controlling the expression of transcription factors. Some lncRNA loci function in trans, but most function in cis, through their own transcription or through the lncRNA transcripts themselves.

Metabolic reprogramming is a hallmark of cancer. Here, we demonstrate that tumour-associated macrophages (TAMs) enhance the aerobic glycolysis and apoptotic resistance of breast cancer cells via the extracellular vesicle (EV) transmission of a myeloid-specific lncRNA, HIF-1α-stabilizing long noncoding RNA (HISLA). Mechanistically, HISLA blocks the interaction of PHD2 and HIF-1α to inhibit the hydroxylation and degradation of HIF-1α. Reciprocally, lactate released from glycolytic tumour cells upregulates HISLA in macrophages, constituting a feed-forward loop between TAMs and tumour cells. Blocking EV-transmitted HISLA inhibits the glycolysis and chemoresistance of breast cancer in vivo. Clinically, HISLA expression in TAMs is associated with glycolysis, poor chemotherapeutic response and shorter survival of patients with breast cancer. Our study highlights the potential of lncRNAs as signal transducers that are transmitted between immune and tumour cells via EVs to promote cancer aerobic glycolysis. Chen et al. show that tumour-associated macrophages transmit HIF-1α-stabilizing long noncoding RNA through extracellular vesicles to breast cancer cells, thereby enhancing tumour glycolysis and chemoresistance.

Evidence accumulated over the past decade shows that long non-coding RNAs (lncRNAs) are widely expressed and have key roles in gene regulation. Recent studies have begun to unravel how the biogenesis of lncRNAs is distinct from that of mRNAs and is linked with their specific subcellular localizations and functions. Depending on their localization and their specific interactions with DNA, RNA and proteins, lncRNAs can modulate chromatin function, regulate the assembly and function of membraneless nuclear bodies, alter the stability and translation of cytoplasmic mRNAs and interfere with signalling pathways. Many of these functions ultimately affect gene expression in diverse biological and physiopathological contexts, such as in neuronal disorders, immune responses and cancer. Tissue-specific and condition-specific expression patterns suggest that lncRNAs are potential biomarkers and provide a rationale to target them clinically. In this Review, we discuss the mechanisms of lncRNA biogenesis, localization and functions in transcriptional, post-transcriptional and other modes of gene regulation, and their potential therapeutic applications.Recent studies have provided novel insight into the biogenesis of long non-coding RNAs (lncRNAs) and their specific functions. The functions of lncRNAs vary from transcriptional and post-transcriptional gene regulation to the assembly and function of membraneless nuclear bodies, and are relevant to neuronal disorders, immune responses and cancer.

A diverse catalog of long noncoding RNAs (lncRNAs), which lack protein-coding potential, are transcribed from the mammalian genome. They are emerging as important regulators in gene expression networks by controlling nuclear architecture and transcription in the nucleus and by modulating mRNA stability, translation and post-translational modifications in the cytoplasm. In this Review, we highlight recent progress in cellular functions of lncRNAs at the molecular level in mammalian cells. Yao et al. review functions of lncRNAs in controlling chromatin architecture, transcription and nuclear bodies in the nucleus and in modulating mRNA stability, translation and protein modifications in the cytoplasm.

Long non-coding RNAs (lncRNAs) have emerged as important regulators of gene expression and plant development. Here, we identified 6,510 lncRNAs in Arabidopsis under normal or stress conditions. We found that the expression of natural antisense transcripts (NATs) that are transcribed in the opposite direction of protein-coding genes often positively correlates with and is required for the expression of their cognate sense genes. We further characterized MAS , a NAT-lncRNA produced from the MADS AFFECTING FLOWERING4 ( MAF4) locus. MAS is induced by cold and indispensable for the activation of MAF4 transcription and suppression of precocious flowering. MAS activates MAF4 by interacting with WDR5a, one core component of the COMPASS-like complexes, and recruiting WDR5a to MAF4 to enhance histone 3 lysine 4 trimethylation (H3K4me3). Our study greatly extends the repertoire of lncRNAs in Arabidopsis and reveals a role for NAT-lncRNAs in regulating gene expression in vernalization response and likely in other biological processes. Long non-coding RNAs regulate developmental transitions and stress responses in plants. Here Zhao et al. show that a non-coding antisense transcript MAS transcribed from the Arabidopsis MAF4 locus activates H3K4me3 deposition and MAF4 transcription to suppress precocious flowering.

X-chromosome inactivation (XCI) is the epigenetic mechanism that ensures X-linked dosage compensation between cells of females (XX karyotype) and males (XY). XCI is essential for female embryos to survive through development and requires the accurate spatiotemporal regulation of many different factors to achieve remarkable chromosome-wide gene silencing. As a result of XCI, the active and inactive X chromosomes are functionally and structurally different, with the inactive X chromosome undergoing a major conformational reorganization within the nucleus. In this Review, we discuss the multiple layers of genetic and epigenetic regulation that underlie initiation of XCI during development and then maintain it throughout life, in light of the most recent findings in this rapidly advancing field. We discuss exciting new insights into the regulation of X inactive-specific transcript (XIST), the trigger and master regulator of XCI, and into the mechanisms and dynamics that underlie the silencing of nearly all X-linked genes. Finally, given the increasing interest in understanding the impact of chromosome organization on gene regulation, we provide an overview of the factors that are thought to reshape the 3D structure of the inactive X chromosome and of the relevance of such structural changes for XCI establishment and maintenance.X chromosome inactivation in mammals involves chromosome-wide gene silencing at one X chromosome in cells of females, a process that requires complex spatiotemporal regulation. Recent findings provide new insights into the mechanisms and dynamics of X chromosome inactivation and the accompanying 3D reshaping of the chromosome.

Long intergenic non-coding RNA (lincRNA) genes have diverse features that distinguish them from mRNA-encoding genes and exercise functions such as remodelling chromatin and genome architecture, RNA stabilization and transcription regulation, including enhancer-associated activity. Some genes currently annotated as encoding lincRNAs include small open reading frames (smORFs) and encode functional peptides and thus may be more properly classified as coding RNAs. lincRNAs may broadly serve to fine-tune the expression of neighbouring genes with remarkable tissue specificity through a diversity of mechanisms, highlighting our rapidly evolving understanding of the non-coding genome.

Key Points Although long non-coding RNAs (lncRNAs) and mRNAs share many common features, several types of lncRNAs are distinguished from mRNAs by unique features of biogenesis, form and function. lncRNAs exhibit more highly specific expression patterns than mRNAs. Many lncRNAs undergo special processing events, such as backspliced circularization, 5′- and 3′-bookending by processed small nucleolar RNAs (snoRNAs), and cleavage by RNase P. lncRNAs are more enriched in the nucleus than the cytoplasm relative to mRNAs, and although cytoplasmic lncRNAs associate with the ribosome, few are productively translated. Certain classes of lncRNAs are preferentially subject to degradation by nonsense-mediated decay and the nuclear exosome, and the elongation of divergent ncRNA transcripts is co-transcriptionally terminated by premature polyadenylation. lncRNAs are uniquely capable of cis action on the genome and chromatin. This feature of lncRNAs enables such biological phenomena as gene imprinting, dosage compensation of sex chromosomes, transcriptional enhancement, chromosome looping and antisense regulation. Long non-coding RNAs (lncRNAs) are a class of RNAs with great molecular and regulatory diversity. This Review discusses how, beyond their lack of protein-coding potential, some types of lncRNAs are known to exhibit features that are distinct from mRNAs, including their transcriptional regulation, localization, processing, biological capabilities and degradation. Such properties underlie many of the key cellular functions of lncRNAs. Long non-coding RNAs (lncRNAs) are a diverse class of RNAs that engage in numerous biological processes across every branch of life. Although initially discovered as mRNA-like transcripts that do not encode proteins, recent studies have revealed features of lncRNAs that further distinguish them from mRNAs. In this Review, we describe special events in the lifetimes of lncRNAs — before, during and after transcription — and discuss how these events ultimately shape the unique characteristics and functional roles of lncRNAs.