Article

Long noncoding RNAs: Functional surprises from the RNA world

Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Genes & development (Impact Factor: 12.64). 08/2009; 23(13):1494-504. DOI: 10.1101/gad.1800909
Source: PubMed

ABSTRACT Most of the eukaryotic genome is transcribed, yielding a complex network of transcripts that includes tens of thousands of long noncoding RNAs with little or no protein-coding capacity. Although the vast majority of long noncoding RNAs have yet to be characterized thoroughly, many of these transcripts are unlikely to represent transcriptional "noise" as a significant number have been shown to exhibit cell type-specific expression, localization to subcellular compartments, and association with human diseases. Here, we highlight recent efforts that have identified a myriad of molecular functions for long noncoding RNAs. In some cases, it appears that simply the act of noncoding RNA transcription is sufficient to positively or negatively affect the expression of nearby genes. However, in many cases, the long noncoding RNAs themselves serve key regulatory roles that were assumed previously to be reserved for proteins, such as regulating the activity or localization of proteins and serving as organizational frameworks of subcellular structures. In addition, many long noncoding RNAs are processed to yield small RNAs or, conversely, modulate how other RNAs are processed. It is thus becoming increasingly clear that long noncoding RNAs can function via numerous paradigms and are key regulatory molecules in the cell.

1 Follower
 · 
264 Views
    • "lncRNAs target chromatin modification enzymes to add 'tags' to chromatin: the chromatin tags in turn are targeted by protein, small and large RNAs. The Polycomb system proteins (PCGPs), that methylate histones over short (Müller and Kassis 2006) or long (Lee et al. 2006; Schwartz et al. 2006; Wang and Chang 2011) distances, are targeted by direct binding to promoters or repressors or recruited to chromatin by lncRNAs which bind both PGCPs and either other proteins or other RNAs (Khalil et al. 2009; Nagano and Fraser 2011; Wilusz et al. 2009). Although Polycomb is usually associated with gene repression, in some cases it has been recruited to gene activation pathways (Gao et al. 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The evolution of life from the simplest, original form to complex, intelligent animal life occurred through a number of key innovations. Here we present a new tool to analyze these key innovations by proposing that the process of evolutionary innovation may follow one of three underlying processes, namely a Random Walk, a Critical Path, or a Many Paths process, and in some instances may also constitute a "Pull-up the Ladder" event. Our analysis is based on the occurrence of function in modern biology, rather than specific structure or mechanism. A function in modern biology may be classified in this way either on the basis of its evolution or the basis of its modern mechanism. Characterizing key innovations in this way helps identify the likelihood that an innovation could arise. In this paper, we describe the classification, and methods to classify functional features of modern organisms into these three classes based on the analysis of how a function is implemented in modern biology. We present the application of our categorization to the evolution of eukaryotic gene control. We use this approach to support the argument that there are few, and possibly no basic chemical differences between the functional constituents of the machinery of gene control between eukaryotes, bacteria and archaea. This suggests that the difference between eukaryotes and prokaryotes that allows the former to develop the complex genetic architecture seen in animals and plants is something other than their chemistry. We tentatively identify the difference as a difference in control logic, that prokaryotic genes are by default 'on' and eukaryotic genes are by default 'off.' The Many Paths evolutionary process suggests that, from a 'default off' starting point, the evolution of the genetic complexity of higher eukaryotes is a high probability event.
    Journal of Molecular Evolution 07/2015; DOI:10.1007/s00239-015-9688-6 · 1.86 Impact Factor
  • Source
    • "FLJ33360 belongs to the long noncoding RNA class (lncRNA). Functionally, lncRNAs are implicated in diverse aspects of gene expression and protein synthesis including epigenetic regulation and direct transcriptional regulation (Wilusz et al. 2009; Ma et al. 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The goal of this study was to identify the contribution of common genetic variants to Down syndrome-associated atrioventricular septal defect, a severe heart abnormality. Compared to the euploid population, infants with Down syndrome, or trisomy 21, have a 2000-fold increased risk of presenting with atrioventricular septal defects. The cause of this elevated risk remains elusive. Here we present data from the largest heart study conducted to date on a trisomic background using a carefully characterized collection of individuals from extreme ends of the phenotypic spectrum. We performed a genome-wide association study using logistic regression analysis on 452 individuals with Down syndrome, consisting of 210 cases with complete atrioventricular septal defects and 242 controls with structurally normal hearts. No individual variant achieved genome-wide significance. We identified four disomic regions (1p36.3, 5p15.31, 8q22.3, and 17q22) and two trisomic regions on chromosome 21 (around PDXK and KCNJ6 genes) that merit further investigation in large replication studies. Our data show that a few common genetic variants of large effect size (odds ratio > 2.0) do not account for the elevated risk of Down syndrome-associated atrioventricular septal defects. Instead, multiple variants of low-to-moderate effect sizes may contribute to this elevated risk, highlighting the complex genetic architecture of atrioventricular septal defects even in the highly susceptible Down syndrome population. Copyright © 2015 Author et al.
    G3-Genes Genomes Genetics 07/2015; DOI:10.1534/g3.115.019943 · 2.51 Impact Factor
  • Source
    • "Although some lncRNAs are transcribed by RNA polymerase III (Dieci et al. 2007; Kapranov et al. 2007) or produced by partial processing by the snoRNA machinery (Yin et al. 2012; Zhang, Yin, et al. 2014), the majority of lncRNAs shows a clear signature of RNA polymerase II transcription, with the promoters marked by histone H3 lysine 4 trimethylation (H3K4me3) and the transcribed gene bodies marked by histone H3 lysine 36 trimethylation (H3K36me3) (Guttman et al. 2009; Khalil et al. 2009). Although most lncRNAs have not been functionally characterized , those that have been suggest lncRNAs are versatile molecules that can interact with DNA, other RNAs and proteins , either through nucleotide base pairing or through formation of structural domains generated by RNA folding (Wilusz et al. 2009; Poliseno et al. 2010; Salmena et al. 2011; Wang and Chang 2011). As expected for regulatory molecules, lncRNAs display specific spatiotemporal expression patterns, high tissue specificity (Cabili et al. 2011; Djebali et al. 2012; Pauli et al. 2012; Li et al. 2014; Necsulea et al. 2014; Washietl et al. 2014) and can regulate expression of genes in close genomic proximity (cis-acting) or at distance (trans-acting) (Mercer et al. 2009; Ponting et al. 2009; Rinn and Chang 2012; Ulitsky and Bartel 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Long non-coding RNAs (lncRNAs) are important developmental regulators in bilaterian animals. A correlation has been claimed between the lncRNA repertoire expansion and morphological complexity in vertebrate evolution. However, this claim has not been tested by examining morphologically simple animals. Here, we undertake a systematic investigation of lncRNAs in the demosponge Amphimedon queenslandica, a morphologically-simple, early-branching metazoan. We combine RNA-Seq data across multiple developmental stages of Amphimedon with a filtering pipeline to conservatively predict 2,935 lncRNAs. These include intronic overlapping lncRNAs, exonic antisense overlapping lncRNAs, long intergenic ncRNAs and precursors for small RNAs. Sponge lncRNAs are remarkably similar to their bilaterian counterparts in being relatively short with few exons and having low primary sequence conservation relative to protein-coding genes. As in bilaterians, a majority of sponge lncRNAs exhibit typical hallmarks of regulatory molecules, including high temporal specificity and dynamic developmental expression. Specific lncRNA expression profiles correlate tightly with conserved protein-coding genes likely involved in a range of developmental and physiological processes, such as the Wnt signaling pathway. Although the majority of Amphimedon lncRNAs appear to be taxonomically-restricted with no identifiable orthologues, we find a few cases of conservation between demosponges in lncRNAs that are antisense to coding sequences. Based on the high similarity in the structure, organisation and dynamic expression of sponge lncRNAs to their bilaterian counterparts, we propose that these non-coding RNAs are an ancient feature of the metazoan genome. These results are consistent with lncRNAs regulating the development of animals, regardless of their level of morphological complexity.
    Molecular Biology and Evolution 05/2015; DOI:10.1093/molbev/msv117 · 14.31 Impact Factor
Show more