ncRNA Transcription Research Articles

Transcriptional Coupling of Neighboring Genes and Gene Expression Noise: Evidence that Gene Orientation and Noncoding Transcripts Are Modulators of Noise

How is noise in gene expression modulated? Do mechanisms of noise control impact genome organization? In yeast, the expression of one gene can affect that of a very close neighbor. As the effect is highly regionalized, we hypothesize that genes in different orientations will have differing degrees of coupled expression and, in turn, different noise levels. Divergently organized gene pairs, in particular those with bidirectional promoters, have close promoters, maximizing the likelihood that expression of one gene affects the neighbor. With more distant promoters, the same is less likely to hold for gene pairs in nondivergent orientation. Stochastic models suggest that coupled chromatin dynamics will typically result in low abundance-corrected noise (ACN). Transcription of noncoding RNA (ncRNA) from a bidirectional promoter, we thus hypothesize to be a noise-reduction, expression-priming, mechanism. The hypothesis correctly predicts that protein-coding genes with a bidirectional promoter, including those with a ncRNA partner, have lower ACN than other genes and divergent gene pairs uniquely have correlated ACN. Moreover, as predicted, ACN increases with the distance between promoters. The model also correctly predicts ncRNA transcripts to be often divergently transcribed from genes that a priori would be under selection for low noise (essential genes, protein complex genes) and that the latter genes should commonly reside in divergent orientation. Likewise, that genes with bidirectional promoters are rare subtelomerically, cluster together, and are enriched in essential gene clusters is expected and observed. We conclude that gene orientation and transcription of ncRNAs are candidate modulators of noise.

Gene Orientation and Non-coding Transcripts Modulate Noise Levels

Event Abstract Back to Event Gene Orientation and Non-coding Transcripts Modulate Noise Levels Guang-Zhong Wang1*, Martin J. Lercher2 and Laurence D. Hurst3 1 Chinese Academy of Sciences, Institute of Biophysics, China 2 University of Dusseldorf, Germany 3 University of Bath, United Kingdom How is noise in gene expression modulated? Do mechanisms of noise control impact genome organization? In yeast, the expression of one gene can affect that of a very close neighbour. As the effect is highly regionalised, we hypothesise that genes in different orientations will have differing degrees of coupled expression and, in turn, different noise-levels. Divergently organized gene pairs, in particular those with bidirectional promoters, have close promoters, maximizing the likelihood that expression of one gene affects the neighbour. With more distant promoters, the same is less likely to hold for gene pairs in non-divergent orientation. Stochastic models suggest that coupled chromatin dynamics will typically result in low abundance-corrected noise (ACN). Transcription of non-coding RNA (ncRNA) from a bidirectional promoter we thus hypothesise to be a noise-reduction, expression-priming, mechanism. The hypothesis correctly predicts that protein-coding genes with a bidirectional promoter, including those with a ncRNA partner, have lower ACN than other genes and divergent gene pairs uniquely have correlated ACN. Moreover, as predicted, ACN increases with the distance between promoters. The model also correctly predicts ncRNA transcripts to be often divergently transcribed from genes that a priori would be under selection for low noise (essential genes, protein complex genes) and that the latter genes should commonly reside in divergent orientation. Likewise, that genes with bidirectional promoters are rare subtelomerically, cluster together and are enriched in essential gene clusters is expected and observed. We conclude that gene orientation and transcription of ncRNAs are candidate modulators of noise. Keywords: Genomics and genetics Conference: 4th INCF Congress of Neuroinformatics, Boston, United States, 4 Sep - 6 Sep, 2011. Presentation Type: Poster Presentation Topic: Genomics and genetics Citation: Wang G, Lercher M and Hurst L (2011). Gene Orientation and Non-coding Transcripts Modulate Noise Levels. Front. Neuroinform. Conference Abstract: 4th INCF Congress of Neuroinformatics. doi: 10.3389/conf.fninf.2011.08.00052 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 17 Oct 2011; Published Online: 19 Oct 2011. * Correspondence: Dr. Guang-Zhong Wang, Chinese Academy of Sciences, Institute of Biophysics, Beijing, China, guangzhong.wang@picb.ac.cn Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Guang-Zhong Wang Martin J. Lercher Laurence D. Hurst Google Guang-Zhong Wang Martin J. Lercher Laurence D. Hurst Google Scholar Guang-Zhong Wang Martin J. Lercher Laurence D. Hurst PubMed Guang-Zhong Wang Martin J. Lercher Laurence D. Hurst Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Grand Challenges and Opportunities in Deciphering the Role of Non-Coding RNAs in Human Diseases

SPECIALTY GRAND CHALLENGE article Front. Genet., 19 January 2011 | https://doi.org/10.3389/fgene.2011.00001

Chromatin Remodeling around Nucleosome-Free Regions Leads to Repression of Noncoding RNA Transcription

Nucleosome-free regions (NFRs) at the 5' and 3' ends of genes are general sites of transcription initiation for mRNA and noncoding RNA (ncRNA). The presence of NFRs within transcriptional regulatory regions and the conserved location of transcription start sites at NFRs strongly suggest that the regulation of NFRs profoundly affects transcription initiation. To date, multiple factors are known to facilitate transcription initiation by positively regulating the formation and/or size of NFRs in vivo. However, mechanisms to repress transcription by negatively regulating the size of NFRs have not been identified. We identified four distinct classes of NFRs located at the 5' and 3' ends of genes, within open reading frames (ORFs), and far from ORFs. The ATP-dependent chromatin-remodeling enzyme Isw2 was found enriched at all classes of NFRs. Analysis of RNA levels also demonstrated Isw2 is required to repress ncRNA transcription from many of these NFRs. Thus, by the systematic annotation of NFRs across the yeast genome and analysis of ncRNA transcription, we established, for the first time, a mechanism by which NFR size is negatively regulated to repress ncRNA transcription from NFRs. Finally, we provide evidence suggesting that one biological consequence of repression of ncRNA, by Isw2 or by the exosome, is prevention of transcriptional interference of mRNA.

Transcriptional coupling of neighbouring genes and gene expression noise: evidence that gene orientation and non-coding transcripts are modulators of noise

AbstractFor some genes, notably essential genes, expression when expression is needed is vital hence low noise in expression is favourable. For others noise is necessary for coping with stochasticity or for providing dice-like mechanisms to control cell fate. But how is noise in gene expression modulated? We hypothesise that gene orientation may be crucial, as for divergently organized gene pairs expression of one gene could affect chromatin of a neighbour thereby reducing noise. Transcription of antisense non-coding RNA from a shared promoter is similarly argued to be a noise-reduction mechanism. Stochastic simulation models confirm the expectation. The model correctly predicts: that protein coding genes with bi-promoter architecture, including those with a ncRNA partner, have lower noise than other genes; divergent gene pairs uniquely have correlated expression noise; distance between promoters predicts noise; ncRNA divergent transcripts are associated with genes that a priori would be under selection for low noise; essential genes reside in divergent orientation more than expected; bi-promoter pairs are rare subtelomerically, cluster together and are enriched in essential gene clusters. We conclude that gene orientation and transcription of ncRNAs, even if unstable, are candidate modulators of noise levels.

Controlling Transcription with Noncoding RNAs in Mammalian Cells

Emerging research suggests that long noncoding RNAs (ncRNAs) may play a role in the basic fabric of gene regulation in human cells. Mechanistic studies carried out on a small subset of antisense ncRNAs have begun to link RNA-mediated modifications of DNA and chromatin structure with gene expression, implicating ncRNAs in the regulation of transcription. Meanwhile, genome-wide studies have revealed that transcription of ncRNAs is far more ubiquitous than previously thought and suggest a more pervasive role for ncRNAs. This review will describe the current state of research regarding gene regulation by ncRNAs and highlight major techniques used in the field. Furthermore, the potential for therapeutic applications based on ncRNA regulation will also be discussed.

Genome-wide detection of predicted non-coding RNAs in Rhizobium etli expressed during free-living and host-associated growth using a high-resolution tiling array

BackgroundNon-coding RNAs (ncRNAs) play a crucial role in the intricate regulation of bacterial gene expression, allowing bacteria to quickly adapt to changing environments. In the past few years, a growing number of regulatory RNA elements have been predicted by computational methods, mostly in well-studied γ-proteobacteria but lately in several α-proteobacteria as well. Here, we have compared an extensive compilation of these non-coding RNA predictions to intergenic expression data of a whole-genome high-resolution tiling array in the soil-dwelling α-proteobacterium Rhizobium etli.ResultsExpression of 89 candidate ncRNAs was detected, both on the chromosome and on the six megaplasmids encompassing the R. etli genome. Of these, 11 correspond to functionally well characterized ncRNAs, 12 were previously identified in other α-proteobacteria but are as yet uncharacterized and 66 were computationally predicted earlier but had not been experimentally identified and were therefore classified as novel ncRNAs. The latter comprise 17 putative sRNAs and 49 putative cis-regulatory ncRNAs. A selection of these candidate ncRNAs was validated by RT-qPCR, Northern blotting and 5' RACE, confirming the existence of 4 ncRNAs. Interestingly, individual transcript levels of numerous ncRNAs varied during free-living growth and during interaction with the eukaryotic host plant, pointing to possible ncRNA-dependent regulation of these specialized processes.ConclusionsOur data support the practical value of previous ncRNA prediction algorithms and significantly expand the list of candidate ncRNAs encoded in the intergenic regions of R. etli and, by extension, of α-proteobacteria. Moreover, we show high-resolution tiling arrays to be suitable tools for studying intergenic ncRNA transcription profiles across the genome. The differential expression levels of some of these ncRNAs may indicate a role in adaptation to changing environmental conditions.

Annotating non-coding transcription using functional genomics strategies

Non-coding RNA (ncRNA) transcripts are RNA molecules that do not code for proteins, but elicit function by other mechanisms. The vast majority of RNA produced in a cell is non-coding ribosomal RNA, produced from relatively few loci, however more recently complementary DNA (cDNA) cloning, tag sequencing, and genome tiling array studies suggest that ncRNAs also account for the majority of RNA species produced by a cell. ncRNA based regulation has been referred to as a 'hidden layer' of signals or 'dark matter' that control gene expression in cellular processes by poorly described mechanisms. These terms have appeared as ncRNAs until recently have been ignored by expression profiling and cDNA annotation projects and their mode of action is diverse (e.g. influencing chromatin structure and epigenetics, translational silencing, transcriptional silencing). Here, we highlight recent functional genomics strategies toward identifying and assigning function to ncRNA transcription.

NcRNA transcription makes its mark

ncRNA transcription makes its mark

Stepwise chromatin remodelling by a cascade of transcription initiation of non-coding RNAs

Recent transcriptome analyses using high-density tiling arrays and data from large-scale analyses of full-length complementary DNA libraries by the FANTOM3 consortium demonstrate that many transcripts are non-coding RNAs (ncRNAs). These transcriptome analyses indicate that many of the non-coding regions, previously thought to be functionally inert, are actually transcriptionally active regions with various features. Furthermore, most relatively large ( approximately several kilobases) polyadenylated messenger RNA transcripts are transcribed from regions harbouring little coding potential. However, the function of such ncRNAs is mostly unknown and has been a matter of debate. Here we show that RNA polymerase II (RNAPII) transcription of ncRNAs is required for chromatin remodelling at the fission yeast Schizosaccharomyces pombe fbp1(+) locus during transcriptional activation. The chromatin at fbp1(+) is progressively converted to an open configuration, as several species of ncRNAs are transcribed through fbp1(+). This is coupled with the translocation of RNAPII through the region upstream of the eventual fbp1(+) transcriptional start site. Insertion of a transcription terminator into this upstream region abolishes both the cascade of transcription of ncRNAs and the progressive chromatin alteration. Our results demonstrate that transcription through the promoter region is required to make DNA sequences accessible to transcriptional activators and to RNAPII.

Transcription of bxd Noncoding RNAs Promoted by Trithorax Represses Ubx in cis by Transcriptional Interference

Much of the genome is transcribed into long noncoding RNAs (ncRNAs). Previous data suggested that bithoraxoid (bxd) ncRNAs of the Drosophila bithorax complex (BX-C) prevent silencing of Ultrabithorax (Ubx) and recruit activating proteins of the trithorax group (trxG) to their maintenance elements (MEs). We found that, surprisingly, Ubx and several bxd ncRNAs are expressed in nonoverlapping patterns in both embryos and imaginal discs, suggesting that transcription of these ncRNAs is associated with repression, not activation, of Ubx. Our data rule out siRNA or miRNA-based mechanisms for repression by bxd ncRNAs. Rather, ncRNA transcription itself, acting in cis, represses Ubx. The Trithorax complex TAC1 binds the Ubx coding region in nuclei expressing Ubx, and the bxd region in nuclei not expressing Ubx. We propose that TAC1 promotes the mosaic pattern of Ubx expression by facilitating transcriptional elongation of bxd ncRNAs, which represses Ubx transcription.

Turnover and Function of Noncoding RNA Polymerase II Transcripts

In the past few years, especially since the discovery of RNA interference (RNAi), our understanding of the role of RNA in gene expression has undergone a significant transformation. This change has been brought about by growing evidence that RNA is more complex and transcription more promiscuous than has previously been thought. Many of the new transcripts are of so-called noncoding RNA (ncRNA); i.e., RNA that does not code for proteins such as mRNA, or intrinsic parts of the cellular machinery such as the highly structured RNA components of ribosomes (rRNA) and the small nuclear RNA (snRNA) components of the splicing machinery. It is becoming increasingly apparent that ncRNAs have very important roles in gene expression. This paper focuses on work from our laboratory in which we have investigated the roles and turnover of ncRNA located within the gene pre-mRNA, which we refer to as intragenic ncRNA. Also discussed are some investigations of intergenic ncRNA transcription and how these two classes of ncRNA may interrelate.

Evolutionary patterns of non-coding RNAs

A plethora of new functions of non-coding RNAs (ncRNAs) have been discovered in past few years. In fact, RNA is emerging as the central player in cellular regulation, taking on active roles in multiple regulatory layers from transcription, RNA maturation, and RNA modification to translational regulation. Nevertheless, very little is known about the evolution of this “Modern RNA World” and its components. In this contribution, we attempt to provide at least a cursory overview of the diversity of ncRNAs and functional RNA motifs in non-translated regions of regular messenger RNAs (mRNAs) with an emphasis on evolutionary questions. This survey is complemented by an in-depth analysis of examples from different classes of RNAs focusing mostly on their evolution in the vertebrate lineage. We present a survey of Y RNA genes in vertebrates and study the molecular evolution of the U7 snRNA, the snoRNAs E1/U17, E2, and E3, the Y RNA family, the let-7 microRNA (miRNA) family, and the mRNA-like evf-1 gene. We furthermore discuss the statistical distribution of miRNAs in metazoans, which suggests an explosive increase in the miRNA repertoire in vertebrates. The analysis of the transcription of ncRNAs suggests that small RNAs in general are genetically mobile in the sense that their association with a hostgene (e.g. when transcribed from introns of a mRNA) can change on evolutionary time scales. The let-7 family demonstrates, that even the mode of transcription (as intron or as exon) can change among paralogous ncRNA.

Challenging the dogma: the hidden layer of non-protein-coding RNAs in complex organisms.

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, autopoietic development and phenotypic variation.