Non‐coding RNAs: regulators of disease
TL;DR: The biology of ncRNAs is reviewed, focusing on the fundamental mechanisms by which nc RNAs facilitate normal development and physiology and, when dysfunctional, underpin disease, and the need to move beyond the confines of protein‐coding genes.
Abstract: For 50 years the term 'gene' has been synonymous with regions of the genome encoding mRNAs that are translated into protein. However, recent genome-wide studies have shown that the human genome is pervasively transcribed and produces many thousands of regulatory non-protein-coding RNAs (ncRNAs), including microRNAs, small interfering RNAs, PIWI-interacting RNAs and various classes of long ncRNAs. It is now clear that these RNAs fulfil critical roles as transcriptional and post-transcriptional regulators and as guides of chromatin-modifying complexes. Here we review the biology of ncRNAs, focusing on the fundamental mechanisms by which ncRNAs facilitate normal development and physiology and, when dysfunctional, underpin disease. We also discuss evidence that intergenic regions associated with complex diseases express ncRNAs, as well as the potential use of ncRNAs as diagnostic markers and therapeutic targets. Taken together, these observations emphasize the need to move beyond the confines of protein-coding genes and highlight the fact that continued investigation of ncRNA biogenesis and function will be necessary for a comprehensive understanding of human disease.
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TL;DR: This review highlights the emerging impact of ncRNAs in cancer research, with a particular focus on the mechanisms and functions of lncRNAs.
Abstract: The discovery of numerous non-coding RNA (ncRNA) transcripts in species from yeast to mammals has dramatically altered our understanding of cell biology, especially disease biology such as cancer. In humans, the identification of abundant long ncRNA (lncRNAs) >200 bp in length has catalyzed their characterization as critical components of cancer biology. Recently, roles for lncRNAs as drivers of tumor suppressive and oncogenic functions have appeared in prevalent cancer types, such as breast and prostate cancer. In this review, we will highlight the emerging impact of ncRNAs in cancer research, with a particular focus on the mechanisms and functions of lncRNAs.
1,554 citations
Cites background from "Non‐coding RNAs: regulators of dise..."
...lncRNAs also commonly exhibit splicing of multiple exons into a mature transcript, as do many antisense RNAs, but not RNAs Small ncRNAs The diversity of small ncRNAs has perhaps grown the most; several dozen classes of small ncRNAs have been proposed (10, 11)....
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TL;DR: The emerging functional role of lncRNAs in human cancer is highlighted and molecular mechanisms by which these RNA species function are described, providing insight into the functional roles they may play in tumorigenesis.
Abstract: Long non-coding RNAs (lncRNAs) are emerging as new players in the cancer paradigm demonstrating potential roles in both oncogenic and tumor suppressive pathways. These novel genes are frequently aberrantly expressed in a variety of human cancers, however the biological functions of the vast majority remain unknown. Recently, evidence has begun to accumulate describing the molecular mechanisms by which these RNA species function, providing insight into the functional roles they may play in tumorigenesis. In this review, we highlight the emerging functional role of lncRNAs in human cancer.
1,464 citations
Cites background from "Non‐coding RNAs: regulators of dise..."
...One such player, the newly discovered long non-coding RNA (lncRNA) genes, demonstrate developmental and tissue specific expression patterns, and aberrant regulation in a variety of diseases, including cancer [18-27]....
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TL;DR: Recent advances in understanding of transcriptional regulation are reviewed and how these have provided new insights into transcriptional misregulation in disease are discussed.
1,180 citations
TL;DR: Classification methods of lncRNAs are summarized according to their four major features, namely, genomic location and context, effect exerted on DNA sequences, mechanism of functioning and their targeting mechanism, and the view on potential further studies.
Abstract: Long non-coding RNAs (lncRNAs) have been found to perform various functions in a wide variety of important biological processes. To make easier interpretation of lncRNA functionality and conduct deep mining on these transcribed sequences, it is convenient to classify lncRNAs into different groups. Here, we summarize classification methods of lncRNAs according to their four major features, namely, genomic location and context, effect exerted on DNA sequences, mechanism of functioning and their targeting mechanism. In combination with the presently available function annotations, we explore potential relationships between different classification categories, and generalize and compare biological features of different lncRNAs within each category. Finally, we present our view on potential further studies. We believe that the classifications of lncRNAs as indicated above are of fundamental importance for lncRNA studies, helpful for further investigation of specific lncRNAs, for formulation of new hypothesis based on different features of lncRNA and for exploration of the underlying lncRNA functional mechanisms.
946 citations
Cites background from "Non‐coding RNAs: regulators of dise..."
...Small ncRNAs include many different RNAs, such as microRNAs (miRNAs), small nucleolar RNAs (snoRNAs), piwiRNAs (piRNAs).(8) Undoubtedly, the definition of lncRNA merely based on length is arbitrary....
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TL;DR: Multiple mechanisms by which drugs alter the transcriptional potential of genes are reviewed, including alterations in the accessibility of genes within their native chromatin structure induced by histone tail modifications and DNA methylation, and the regulation of gene expression by non-coding RNAs.
Abstract: Investigations of long-term changes in brain structure and function that accompany chronic exposure to drugs of abuse suggest that alterations in gene regulation contribute substantially to the addictive phenotype. Here, we review multiple mechanisms by which drugs alter the transcriptional potential of genes. These mechanisms range from the mobilization or repression of the transcriptional machinery - including the transcription factors ΔFOSB, cyclic AMP-responsive element binding protein (CREB) and nuclear factor-κB (NF-κB) - to epigenetics - including alterations in the accessibility of genes within their native chromatin structure induced by histone tail modifications and DNA methylation, and the regulation of gene expression by non-coding RNAs. Increasing evidence implicates these various mechanisms of gene regulation in the lasting changes that drugs of abuse induce in the brain, and offers novel inroads for addiction therapy.
864 citations
Cites background from "Non‐coding RNAs: regulators of dise..."
...Increasing attention has focused on a variety of non-coding RNAs that are important in biological regulatio...
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References
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TL;DR: To their surprise, it was found that double-stranded RNA was substantially more effective at producing interference than was either strand individually, arguing against stochiometric interference with endogenous mRNA and suggesting that there could be a catalytic or amplification component in the interference process.
Abstract: Experimental introduction of RNA into cells can be used in certain biological systems to interfere with the function of an endogenous gene Such effects have been proposed to result from a simple antisense mechanism that depends on hybridization between the injected RNA and endogenous messenger RNA transcripts RNA interference has been used in the nematode Caenorhabditis elegans to manipulate gene expression Here we investigate the requirements for structure and delivery of the interfering RNA To our surprise, we found that double-stranded RNA was substantially more effective at producing interference than was either strand individually After injection into adult animals, purified single strands had at most a modest effect, whereas double-stranded mixtures caused potent and specific interference The effects of this interference were evident in both the injected animals and their progeny Only a few molecules of injected double-stranded RNA were required per affected cell, arguing against stochiometric interference with endogenous mRNA and suggesting that there could be a catalytic or amplification component in the interference process
15,374 citations
"Non‐coding RNAs: regulators of dise..." refers background in this paper
...elegans is cleaved by the bidentate ribonuclease Dicer into ∼21 nucleotide (nt) small RNAs that induce widespread and heritable gene silencing [29–31]....
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TL;DR: 21-nucleotide siRNA duplexes provide a new tool for studying gene function in mammalian cells and may eventually be used as gene-specific therapeutics.
Abstract: RNA interference (RNAi) is the process of sequence-specific, post-transcriptional gene silencing in animals and plants, initiated by double-stranded RNA (dsRNA) that is homologous in sequence to the silenced gene. The mediators of sequence-specific messenger RNA degradation are 21- and 22-nucleotide small interfering RNAs (siRNAs) generated by ribonuclease III cleavage from longer dsRNAs. Here we show that 21-nucleotide siRNA duplexes specifically suppress expression of endogenous and heterologous genes in different mammalian cell lines, including human embryonic kidney (293) and HeLa cells. Therefore, 21-nucleotide siRNA duplexes provide a new tool for studying gene function in mammalian cells and may eventually be used as gene-specific therapeutics.
10,451 citations
"Non‐coding RNAs: regulators of dise..." refers background in this paper
...Hopes for RNA-based and RNA-targeted therapies were bolstered by early successes using siRNAs in human in vitro culture systems [206] and in targeting HIV-1 and human BCL2 with siRNA-like molecules [207–209]....
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TL;DR: A new, bead-based flow cytometric miRNA expression profiling method is used to present a systematic expression analysis of 217 mammalian miRNAs from 334 samples, including multiple human cancers, and finds the miRNA profiles are surprisingly informative, reflecting the developmental lineage and differentiation state of the tumours.
Abstract: Recent work has revealed the existence of a class of small non-coding RNA species, known as microRNAs (miRNAs), which have critical functions across various biological processes. Here we use a new, bead-based flow cytometric miRNA expression profiling method to present a systematic expression analysis of 217 mammalian miRNAs from 334 samples, including multiple human cancers. The miRNA profiles are surprisingly informative, reflecting the developmental lineage and differentiation state of the tumours. We observe a general downregulation of miRNAs in tumours compared with normal tissues. Furthermore, we were able to successfully classify poorly differentiated tumours using miRNA expression profiles, whereas messenger RNA profiles were highly inaccurate when applied to the same samples. These findings highlight the potential of miRNA profiling in cancer diagnosis.
9,470 citations
"Non‐coding RNAs: regulators of dise..." refers background or result in this paper
...Indeed, a signature of as few as 200 miRNAs may be sufficient for cancer classification [198], and it appears that some of the difficulties of early detection associated with colon and other occult cancers may be overcome by profiling miRNAs obtained from patient serum, plasma, saliva and tissues [200,201]....
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...For example, in some cases the expression profiles of miRNAs, in contrast to those of protein-coding mRNAs, are able to accurately identify the origin of poorly differentiated tumours and carcinomas [198,199]....
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Ewan Birney, John A. Stamatoyannopoulos1, Anindya Dutta2, Roderic Guigó3 +317 more•Institutions (44)
TL;DR: Functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project are reported, providing convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts.
Abstract: We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
5,091 citations
"Non‐coding RNAs: regulators of dise..." refers background or result in this paper
...An explanation for this apparent paradox comes from two unexpected findings: (a) that biological complexity generally correlates with the proportion of the genome that is non-protein-coding [1]; and (b) that, while only 2% of the mammalian genome encodes mRNAs, the vast majority is transcribed, largely as long and short non-protein-coding RNAs (ncRNAs) [2–10]....
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...Genome-wide transcriptomic studies have now shown that the mammalian genome is abundantly transcribed [2–10] and that at least 80% of this transcription is exclusively associated with long non-coding RNAs (lncRNAs) [9]....
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TL;DR: The rapidly advancing field of long ncRNAs is reviewed, describing their conservation, their organization in the genome and their roles in gene regulation, and the medical implications.
Abstract: In mammals and other eukaryotes most of the genome is transcribed in a developmentally regulated manner to produce large numbers of long non-coding RNAs (ncRNAs). Here we review the rapidly advancing field of long ncRNAs, describing their conservation, their organization in the genome and their roles in gene regulation. We also consider the medical implications, and the emerging recognition that any transcript, regardless of coding potential, can have an intrinsic function as an RNA.
4,911 citations
"Non‐coding RNAs: regulators of dise..." refers background in this paper
...Their functions include epigenetic regulation, acting as sequence-specific tethers for protein complexes and specifying subcellular compartments or localization Reviewed in [97,98]...
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...Indeed, they are frequently long (generally >2 and some >100 kb) [96], spliced and contain canonical polyadenylation signals [97,98]....
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