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Regulatory Roles for Long ncRNA and mRNA  [PDF]
Armen R. Karapetyan,Coen Buiting,Renske A. Kuiper,Marcel W. Coolen
Cancers , 2013, DOI: 10.3390/cancers5020462
Abstract: Recent advances in high-throughput sequencing technology have identified the transcription of a much larger portion of the genome than previously anticipated. Especially in the context of cancer it has become clear that aberrant transcription of both protein-coding and long non-coding RNAs (lncRNAs) are frequent events. The current dogma of RNA function describes mRNA to be responsible for the synthesis of proteins, whereas non-coding RNA can have regulatory or epigenetic functions. However, this distinction between protein coding and regulatory ability of transcripts may not be that strict. Here, we review the increasing body of evidence for the existence of multifunctional RNAs that have both protein-coding and trans-regulatory roles. Moreover, we demonstrate that coding transcripts bind to components of the Polycomb Repressor Complex 2 (PRC2) with similar affinities as non-coding transcripts, revealing potential epigenetic regulation by mRNAs. We hypothesize that studies on the regulatory ability of disease-associated mRNAs will form an important new field of research.
Dog eat dogma
Gregory A Petsko
Genome Biology , 2000, DOI: 10.1186/gb-2000-1-2-comment1002
Abstract: Few statements in biology have been as sweeping as the 'Central Dogma of Molecular Biology': DNA makes RNA makes protein. Its name is always capitalized, like the Constitution of the United States or the Magna Carta. It is usually stated without qualification. It was referred to, from its inception, as a dogma rather than a theory. (Even Darwin had the modesty to call evolution a theory.) Scientists don't usually produce dogmas; that is nominally the province of religions, and even the briefest study of history will suggest that, in addition to admitting of no contradiction, dogmas tend to be accompanied by lots of other fun things, such as inquisitions and wars.The Central Dogma was beloved of students because it was easy to remember and had no stated exceptions, like any good dogma. Sadly, it has fallen on hard times of late. The discovery of reverse transcriptase provided an inconvenient example of the synthesis of DNA from RNA. An attempt was made to re-establish dogma status by explaining that the phrase 'DNA makes RNA makes protein' really referred to the flow of genetic information, not the actual steps of synthesis. Then along came RNA editing, in which guide RNAs or enzyme action modify some messenger RNAs such that the final protein sequence cannot be deduced from the gene sequence alone. Alternative splicing didn't help either: it could be argued that it represents a case of RNA making itself, then making a bunch of different proteins. And then there was that inconvenient stuff about RNA catalysis, which suggested that there was once an RNA world in which RNA made protein without DNA getting into the act at all. To account for all this, the Central Dogma now would have to go something like this: 'DNA makes RNA makes protein, but sometimes RNA can make DNA and other times RNA makes RNA, which makes proteins different from what they would be if only DNA made the RNA, and once upon a time RNA made protein, probably, but no-one knows for certain'. Or, if you
Disease-Associated Mutations That Alter the RNA Structural Ensemble  [PDF]
Matthew Halvorsen,Joshua S. Martin,Sam Broadaway,Alain Laederach
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1001074
Abstract: Genome-wide association studies (GWAS) often identify disease-associated mutations in intergenic and non-coding regions of the genome. Given the high percentage of the human genome that is transcribed, we postulate that for some observed associations the disease phenotype is caused by a structural rearrangement in a regulatory region of the RNA transcript. To identify such mutations, we have performed a genome-wide analysis of all known disease-associated Single Nucleotide Polymorphisms (SNPs) from the Human Gene Mutation Database (HGMD) that map to the untranslated regions (UTRs) of a gene. Rather than using minimum free energy approaches (e.g. mFold), we use a partition function calculation that takes into consideration the ensemble of possible RNA conformations for a given sequence. We identified in the human genome disease-associated SNPs that significantly alter the global conformation of the UTR to which they map. For six disease-states (Hyperferritinemia Cataract Syndrome, β-Thalassemia, Cartilage-Hair Hypoplasia, Retinoblastoma, Chronic Obstructive Pulmonary Disease (COPD), and Hypertension), we identified multiple SNPs in UTRs that alter the mRNA structural ensemble of the associated genes. Using a Boltzmann sampling procedure for sub-optimal RNA structures, we are able to characterize and visualize the nature of the conformational changes induced by the disease-associated mutations in the structural ensemble. We observe in several cases (specifically the 5′ UTRs of FTL and RB1) SNP–induced conformational changes analogous to those observed in bacterial regulatory Riboswitches when specific ligands bind. We propose that the UTR and SNP combinations we identify constitute a “RiboSNitch,” that is a regulatory RNA in which a specific SNP has a structural consequence that results in a disease phenotype. Our SNPfold algorithm can help identify RiboSNitches by leveraging GWAS data and an analysis of the mRNA structural ensemble.
Canonical A-to-I and C-to-U RNA Editing Is Enriched at 3′UTRs and microRNA Target Sites in Multiple Mouse Tissues  [PDF]
Tongjun Gu, Frank W. Buaas, Allen K. Simons, Cheryl L. Ackert-Bicknell, Robert E. Braun, Matthew A. Hibbs
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033720
Abstract: RNA editing is a process that modifies RNA nucleotides and changes the efficiency and fidelity of the central dogma. Enzymes that catalyze RNA editing are required for life, and defects in RNA editing are associated with many diseases. Recent advances in sequencing have enabled the genome-wide identification of RNA editing sites in mammalian transcriptomes. Here, we demonstrate that canonical RNA editing (A-to-I and C-to-U) occurs in liver, white adipose, and bone tissues of the laboratory mouse, and we show that apparent non-canonical editing (all other possible base substitutions) is an artifact of current high-throughput sequencing technology. Further, we report that high-confidence canonical RNA editing sites can cause non-synonymous amino acid changes and are significantly enriched in 3′ UTRs, specifically at microRNA target sites, suggesting both regulatory and functional consequences for RNA editing.
HrpA, an RNA Helicase Involved in RNA Processing, Is Required for Mouse Infectivity and Tick Transmission of the Lyme Disease Spirochete  [PDF]
Aydan Salman-Dilgimen,Pierre-Olivier Hardy,Justin D. Radolf,Melissa J. Caimano,George Chaconas
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003841
Abstract: The Lyme disease spirochete Borrelia burgdorferi must differentially express genes and proteins in order to survive in and transit between its tick vector and vertebrate reservoir. The putative DEAH-box RNA helicase, HrpA, has been recently identified as an addition to the spirochete's global regulatory machinery; using proteomic methods, we demonstrated that HrpA modulates the expression of at least 180 proteins. Although most bacteria encode an HrpA helicase, RNA helicase activity has never been demonstrated for HrpAs and the literature contains little information on the contribution of this protein to bacterial physiology or pathogenicity. In this work, we report that B. burgdorferi HrpA has RNA-stimulated ATPase activity and RNA helicase activity and that this enzyme is essential for both mammalian infectivity by syringe inoculation and tick transmission. Reduced infectivity of strains carrying mutations in the ATPase and RNA binding motif mutants suggests that full virulence expression requires both ATPase and coupled helicase activity. Microarray profiling revealed changes in RNA levels of two-fold, or less in an hrpA mutant versus wild-type, suggesting that the enzyme functions largely or exclusively at the post-transcriptional level. In this regard, northern blot analysis of selected gene products highly regulated by HrpA (bb0603 [p66], bba74, bb0241 [glpK], bb0242 and bb0243 [glpA]) suggests a role for HrpA in the processing and translation of transcripts. In addition to being the first demonstration of RNA helicase activity for a bacterial HrpA, our data indicate that the post-transcriptional regulatory functions of this enzyme are essential for maintenance of the Lyme disease spirochete's enzootic cycle.
Messenger RNA Fluctuations and Regulatory RNAs Shape the Dynamics of Negative Feedback Loop  [PDF]
María Rodríguez Martínez,Jordi Soriano,Tsvi Tlusty,Yitzhak Pilpel,Itay Furman
Quantitative Biology , 2010, DOI: 10.1103/PhysRevE.81.031924
Abstract: Single cell experiments of simple regulatory networks can markedly differ from cell population experiments. Such differences arise from stochastic events in individual cells that are averaged out in cell populations. For instance, while individual cells may show sustained oscillations in the concentrations of some proteins, such oscillations may appear damped in the population average. In this paper we investigate the role of RNA stochastic fluctuations as a leading force to produce a sustained excitatory behavior at the single cell level. Opposed to some previous models, we build a fully stochastic model of a negative feedback loop that explicitly takes into account the RNA stochastic dynamics. We find that messenger RNA random fluctuations can be amplified during translation and produce sustained pulses of protein expression. Motivated by the recent appreciation of the importance of non--coding regulatory RNAs in post--transcription regulation, we also consider the possibility that a regulatory RNA transcript could bind to the messenger RNA and repress translation. Our findings show that the regulatory transcript helps reduce gene expression variability both at the single cell level and at the cell population level.
Comparative genomics of small RNA regulatory pathway components in vector mosquitoes
Corey L Campbell, William C Black, Ann M Hess, Brian D Foy
BMC Genomics , 2008, DOI: 10.1186/1471-2164-9-425
Abstract: The Ae. aegypti, An. gambiae and Cx. pipiens genomes encode putative orthologs for all major components of the miRNA, siRNA, and piRNA pathways. Ae. aegypti and Cx. pipiens have undergone expansion of Argonaute and PIWI subfamily genes. Phylogenetic analyses were performed for these protein families. In addition, sequence pattern recognition algorithms MEME, MDScan and Weeder were used to identify upstream regulatory motifs for all SRRP components. Statistical analyses confirmed enrichment of species-specific and pathway-specific cis-elements over the rest of the genome.Analysis of Argonaute and PIWI subfamily genes suggests that the small regulatory RNA pathways of the major arbovirus vectors, Ae. aegypti and Cx. pipiens, are evolving faster than those of the malaria vector An. gambiae and D. melanogaster. Further, protein and genomic features suggest functional differences between subclasses of PIWI proteins and provide a basis for future analyses. Common UCR elements among SRRP components indicate that 1) key components from the miRNA, siRNA, and piRNA pathways contain NF-kappaB-related and Broad complex transcription factor binding sites, 2) purifying selection has occurred to maintain common pathway-specific elements across mosquito species and 3) species-specific differences in upstream elements suggest that there may be differences in regulatory control among mosquito species. Implications for arbovirus vector competence in mosquitoes are discussed.Small RNA-mediated gene silencing pathways are master regulators of critical cellular processes, from development to germ-line surveillance to anti-viral defense [1-5]. Although small RNA regulatory pathways (SRRPs) operate using distinctly different mechanisms, they share several common features. Small regulatory RNAs of 20 to 30 nucleotides (nts) are used as guide strands for target substrate recognition by an RNase H type nuclease of the Argonaute protein family. Target RNAs are subsequently degraded or otherwis
Evolution and distribution of RNA polymerase II regulatory sites from RNA polymerase III dependant mobile Alu elements
Ravi Shankar, Deepak Grover, Samir K Brahmachari, Mitali Mukerji
BMC Evolutionary Biology , 2004, DOI: 10.1186/1471-2148-4-37
Abstract: We conducted a retrospective analysis of putative functional sites, such as the RNA pol III promoter elements, pol II regulatory elements like hormone responsive elements and ligand-activated receptor binding sites, in Alus of various evolutionary ages. We observe a progressive loss of the RNA pol III transcriptional potential with concomitant accumulation of RNA pol II regulatory sites. We also observe a significant over-representation of Alus harboring these sites in promoter regions of signaling and metabolism genes of chromosome 22, when compared to genes of information pathway components, structural and transport proteins. This difference is not so significant between functional categories in the intronic regions of the same genes.Our study clearly suggests that Alu elements, through retrotransposition, could distribute functional and regulatable promoter elements, which in the course of subsequent selection might be stabilized in the genome. Exaptation of regulatory elements in the preexisting genes through Alus could thus have contributed to evolution of novel regulatory networks in the primate genomes. With such a wide spectrum of regulatory sites present in Alus, it also becomes imperative to screen for variations in these sites in candidate genes, which are otherwise repeat-masked in studies pertaining to identification of predisposition markers.In the post genome sequence era, repetitive sequences, erstwhile considered junk and devoid of function, are increasingly being implicated in many cellular functions, genome organization and diseases [1-8]. Alu repeats, which belong to SINE (short interspersed nucleotide elements) family of repetitive sequences, are present exclusively in the primate genomes. These elements which are ~300 bps in length have originated from the 7SL RNA gene and comprise of two similar, but not identical subunits [9-12]. Each element contains a bipartite promoter for RNA polymerase III, a poly (A) tract located between the monomers,
Regulatory T Cells and Human Disease  [PDF]
Nathalie Cools,Peter Ponsaerts,Viggo F. I. Van Tendeloo,Zwi N. Berneman
Clinical and Developmental Immunology , 2007, DOI: 10.1155/2007/89195
Abstract: The main function of our immune system is to protect us from invading pathogens and microorganisms bydestroying infected cells, while minimizing collateral damage to tissues. In order to maintain this balance betweenimmunity and tolerance, current understanding of the immune system attributes a major role to regulatory T cells(Tregs) in controlling both immunity and tolerance. Various subsets of Tregs have been identified based on theirexpression of cell surface markers, production of cytokines, and mechanisms of action. In brief, naturally occurringthymic-derived CD4
Regulatory RNAs and the demise of 'junk' DNA
Frank J Slack
Genome Biology , 2006, DOI: 10.1186/gb-2006-7-9-328
Abstract: A growing body of work suggests that genes for noncoding RNAs make up a substantial class of genes in all organisms, with increasing organismal complexity correlated with an increasing complexity of noncoding RNAs. Many of these noncoding RNAs appear to have regulatory functions and these were the subject of this year's annual Cold Spring Harbor Symposium. Among the most exciting themes of the meeting were the evidence for significant amounts of hitherto undiscovered transcription in genomes and the discovery of novel classes of noncoding RNAs with thousands of members. In this report I review a few of these highlights.The tenets of the 'central dogma' have required revision over the past few decades as biologists have begun to appreciate that RNA performs many functions once thought solely to be the domain of proteins. Apart from its well established roles as messenger, ribosomal component, and transfer RNA, it is now clear that RNA can have a key role in regulating gene expression. Noncoding regulatory RNAs - RNAs that are not translated into protein - include the small nuclear RNAs (snRNAs), the small nucleolar RNAs (snoRNAs), the XIST RNA that mediates mammalian X-chromosome silencing, microRNAs, riboswitches, and the RNA component of the enzyme telomerase. These RNAs direct such diverse processes as gene silencing, transcriptional and translational control, imprinting, and dosage compensation. These discoveries have electrified the biological community as we try to understand the extent of the 'RNA world' and how regulatory RNAs work in controlling gene expression. We are fast learning that large portions of the genome that do not code for proteins are in fact transcribed, and that these regions, previously thought to be 'junk', may be useful after all (Figure 1).Whole-genome tiling microarrays offer a relatively unbiased and sensitive approach to detecting rare transcripts and, along with the sequencing of expressed sequence tags (ESTs), are providing ample ev
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