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Journal ArticleDOI

How do lncRNAs regulate transcription

01 Sep 2017-Science Advances (American Association for the Advancement of Science)-Vol. 3, Iss: 9
TL;DR: Recent progress in elucidating the molecular mechanisms by which lncRNAs modulate gene expression is reviewed, including the act of lnc RNA transcription rather than the lncRNA product that appears to be regulatory.
Abstract: It has recently become apparent that RNA, itself the product of transcription, is a major regulator of the transcriptional process. In particular, long noncoding RNAs (lncRNAs), which are so numerous in eukaryotes, function in many cases as transcriptional regulators. These RNAs function through binding to histone-modifying complexes, to DNA binding proteins (including transcription factors), and even to RNA polymerase II. In other cases, it is the act of lncRNA transcription rather than the lncRNA product that appears to be regulatory. We review recent progress in elucidating the molecular mechanisms by which lncRNAs modulate gene expression and future opportunities in this research field.
Citations
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Journal ArticleDOI
TL;DR: This Review focuses on the current state of knowledge pertaining to packaging, transport and function of RNAs in extracellular vesicles and outlines the progress made thus far towards their clinical applications.
Abstract: The term 'extracellular vesicles' refers to a heterogeneous population of vesicular bodies of cellular origin that derive either from the endosomal compartment (exosomes) or as a result of shedding from the plasma membrane (microvesicles, oncosomes and apoptotic bodies). Extracellular vesicles carry a variety of cargo, including RNAs, proteins, lipids and DNA, which can be taken up by other cells, both in the direct vicinity of the source cell and at distant sites in the body via biofluids, and elicit a variety of phenotypic responses. Owing to their unique biology and roles in cell-cell communication, extracellular vesicles have attracted strong interest, which is further enhanced by their potential clinical utility. Because extracellular vesicles derive their cargo from the contents of the cells that produce them, they are attractive sources of biomarkers for a variety of diseases. Furthermore, studies demonstrating phenotypic effects of specific extracellular vesicle-associated cargo on target cells have stoked interest in extracellular vesicles as therapeutic vehicles. There is particularly strong evidence that the RNA cargo of extracellular vesicles can alter recipient cell gene expression and function. During the past decade, extracellular vesicles and their RNA cargo have become better defined, but many aspects of extracellular vesicle biology remain to be elucidated. These include selective cargo loading resulting in substantial differences between the composition of extracellular vesicles and source cells; heterogeneity in extracellular vesicle size and composition; and undefined mechanisms for the uptake of extracellular vesicles into recipient cells and the fates of their cargo. Further progress in unravelling the basic mechanisms of extracellular vesicle biogenesis, transport, and cargo delivery and function is needed for successful clinical implementation. This Review focuses on the current state of knowledge pertaining to packaging, transport and function of RNAs in extracellular vesicles and outlines the progress made thus far towards their clinical applications.

788 citations

Journal ArticleDOI
TL;DR: Key aspects of lncRNA biology are reviewed, focusing on their role as regulatory elements in gene expression modulation during physiological and disease processes, with implications in host and pathogens physiology, and their role in immune response modulation.
Abstract: The identification of RNAs that are not translated into proteins was an important breakthrough, defining the diversity of molecules involved in eukaryotic regulation of gene expression. These non-coding RNAs can be divided into two main classes according to their length: short non-coding RNAs, such as microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). The lncRNAs in association with other molecules can coordinate several physiological processes and their dysfunction may impact in several pathologies, including cancer and infectious diseases. They can control the flux of genetic information, such as chromosome structure modulation, transcription, splicing, messenger RNA (mRNA) stability, mRNA availability, and post-translational modifications. Long non-coding RNAs present interaction domains for DNA, mRNAs, miRNAs, and proteins, depending on both sequence and secondary structure. The advent of new generation sequencing has provided evidences of putative lncRNAs existence; however, the analysis of transcriptomes for their functional characterization remains a challenge. Here, we review some important aspects of lncRNA biology, focusing on their role as regulatory elements in gene expression modulation during physiological and disease processes, with implications in host and pathogens physiology, and their role in immune response modulation.

403 citations


Cites background from "How do lncRNAs regulate transcripti..."

  • ...Other lncRNAs can regulate transcription, controlling DNA methyltransferases recruitment, TFs, zinc-finger proteins, and others transcription regulators [1]....

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  • ...Long non-coding RNAs are found within the nucleus, nucleolus, cytoplasm, and even in the mitochondria [38,39], and its localization is a good indicator of their mode of action [1], as shown in Figure 2....

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  • ...The discrepancy of about 20,000 protein-coding genes and over 100,000 different transcripts identified in mammalian transcriptomes highlights the possibility of discovering a novel class of non-translated RNAs [1], beyond those already identified in the 1970s, as part of the translation machinery: ribosomal RNAs (rRNAs) [2] and transfer RNAs (tRNAs) [3]....

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  • ...The most recent NONCODE database source points to over 100,000 lncRNAs in the human genome, but this number seems to be underestimated [1,30,31]....

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Journal ArticleDOI
TL;DR: This review discusses the distinct types of ncRNAs, including housekeeping n cRNAs and regulatory nc RNAs, their versatile functions and interactions, transcription, translation, and modification, and summarizes the integrated networks of n cRNA interactions, providing a comprehensive landscape of nCRNAs regulatory roles.
Abstract: Eukaryotic genomes are pervasively transcribed. Besides protein-coding RNAs, there are different types of non-coding RNAs that modulate complex molecular and cellular processes. RNA sequencing technologies and bioinformatics methods greatly promoted the study of ncRNAs, which revealed ncRNAs' essential roles in diverse aspects of biological functions. As important key players in gene regulatory networks, ncRNAs work with other biomolecules, including coding and non-coding RNAs, DNAs and proteins. In this review, we discuss the distinct types of ncRNAs, including housekeeping ncRNAs and regulatory ncRNAs, their versatile functions and interactions, transcription, translation, and modification. Moreover, we summarize the integrated networks of ncRNA interactions, providing a comprehensive landscape of ncRNAs regulatory roles.

282 citations

Journal ArticleDOI
TL;DR: The current status of knowledge on lncRNAs classification, biogenesis and its role in blood cells is summarized.

245 citations

Journal ArticleDOI
TL;DR: In this paper, the authors discuss latest developments in lncRNA-meditated gene expression at the post-transcriptional level, including gene splicing, mRNA stability, protein stability and nuclear trafficking.
Abstract: Accumulating evidence indicates that long non-coding RNAs (lncRNAs) can play a pivotal role in regulation of diverse cellular processes. In particular, lncRNAs can serve as master gene regulators at transcriptional and posttranscriptional levels, leading to tumorigenesis. In this review, we discuss latest developments in lncRNA-meditated gene expression at the post-transcriptional level, including gene splicing, mRNA stability, protein stability and nuclear trafficking.

148 citations

References
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Journal ArticleDOI
28 Feb 2013-Cell
TL;DR: This RNA-guided DNA recognition platform provides a simple approach for selectively perturbing gene expression on a genome-wide scale and can efficiently repress expression of targeted genes in Escherichia coli, with no detectable off-target effects.

4,282 citations


"How do lncRNAs regulate transcripti..." refers background in this paper

  • ...Inserting multiple polyadenylation sequences downstream from a lncRNA promoter and interfering with lncRNA transcription using CRISPR interference (159) are more surgically incisive, but negative results must be interpreted with caution because these techniques truncate rather than eliminate lncRNA transcription....

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Journal ArticleDOI
06 Aug 2010-Science
TL;DR: The results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes.
Abstract: Long intergenic noncoding RNAs (lincRNAs) regulate chromatin states and epigenetic inheritance. Here, we show that the lincRNA HOTAIR serves as a scaffold for at least two distinct histone modification complexes. A 5' domain of HOTAIR binds polycomb repressive complex 2 (PRC2), whereas a 3' domain of HOTAIR binds the LSD1/CoREST/REST complex. The ability to tether two distinct complexes enables RNA-mediated assembly of PRC2 and LSD1 and coordinates targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation and lysine 4 demethylation. Our results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes.

2,946 citations

Journal ArticleDOI
27 Mar 2014-Cell
TL;DR: The pathway of ncRNA research is described, where every established "rule" seems destined to be overturned.

1,875 citations


"How do lncRNAs regulate transcripti..." refers background in this paper

  • ...(3) Indirectly, through the act of transcription Transcription of a lncRNA may regulate the transcription of nearby mRNAgenes, either positively (maintaining active chromatin structure) or negatively (for example, colliding polymerases)....

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  • ...Some lncRNAs may function at the RNA level, for example, as ribozymes or riboswitches (3)....

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Journal ArticleDOI
01 Dec 1996-Nature
TL;DR: It is shown that CBP has intrinsic HAT activity, and Targeting CBP-associated H AT activity to specific promoters may be a mechanism by which E1A acts as a transcriptional activator.
Abstract: The CBP protein acts as a transcriptional adaptor for many different transcription factors by directly contacting DNA-bound activators. One mechanism by which CBP is thought to stimulate transcription is by recruiting the histone acetyltransferase (HAT) P/CAF to the promoter. Here we show that CBP has intrinsic HAT activity. The HAT domain of CBP is adjacent to the binding site for the transcriptional activator E1A. Although E1A displaces P/CAF from CBP, it does not disrupt the CBP-associated HAT activity. Thus E1A carries HAT activity when complexed with CBP. Targeting CBP-associated HAT activity to specific promoters may therefore be a mechanism by which E1A acts as a transcriptional activator.

1,783 citations

Journal ArticleDOI
07 Apr 2011-Nature
TL;DR: OTTIP RNA binds the adaptor protein WDR5 directly and targets WDR 5/MLL complexes across HOXA, driving histone H3 lysine 4 trimethylation and gene transcription.
Abstract: A major question in developmental biology is how functionally related groups of genes are switched on at the right time and in the right place. Long intergenic non-coding RNAs (lincRNAs) have been implicated in both gene silencing and activation, and could be a means of long-range control of gene expression. A lincRNA termed HOTTIP that coordinates the activation of multiple 5' HOXA regulatory genes has now been identified at the 5' tip of the HOXA locus. Chromosomal looping brings HOTTIP close its target genes, where it facilitates histone H3 lysine 4 trimethylation and gene transcription. Long intergenic non-coding RNAs (lincRNAs) have been implicated in both gene silencing and activation, and could be a means for long-range control of gene expression. Here a lincRNA termed HOTTIP is identified at the 5′ tip of the HOXA locus that coordinates the activation of multiple 5′ HOXA genes. Chromosomal looping brings HOTTIP into the proximity of its target genes, where it seems to be required to facilitate histone H3 lysine 4 trimethylation and gene transcription. The genome is extensively transcribed into long intergenic noncoding RNAs (lincRNAs), many of which are implicated in gene silencing1,2. Potential roles of lincRNAs in gene activation are much less understood3,4,5. Development and homeostasis require coordinate regulation of neighbouring genes through a process termed locus control6. Some locus control elements and enhancers transcribe lincRNAs7,8,9,10, hinting at possible roles in long-range control. In vertebrates, 39 Hox genes, encoding homeodomain transcription factors critical for positional identity, are clustered in four chromosomal loci; the Hox genes are expressed in nested anterior-posterior and proximal-distal patterns colinear with their genomic position from 3′ to 5′of the cluster11. Here we identify HOTTIP, a lincRNA transcribed from the 5′ tip of the HOXA locus that coordinates the activation of several 5′ HOXA genes in vivo. Chromosomal looping brings HOTTIP into close proximity to its target genes. HOTTIP RNA binds the adaptor protein WDR5 directly and targets WDR5/MLL complexes across HOXA, driving histone H3 lysine 4 trimethylation and gene transcription. Induced proximity is necessary and sufficient for HOTTIP RNA activation of its target genes. Thus, by serving as key intermediates that transmit information from higher order chromosomal looping into chromatin modifications, lincRNAs may organize chromatin domains to coordinate long-range gene activation.

1,782 citations

Related Papers (5)
06 Sep 2012-Nature