What are Long or large non-coding RNAs (lncRNAs)?


Long or large non-coding RNAs (lncRNAs) are non-protein coding sequence transcripts !

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Long non-coding RNAs are non-protein coding sequence transcripts that contain more than 200 nucleotides. The size of these RNA molecules distinguishes them from small regulatory RNAs such as microRNAs (miRNAs), short interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), short hairpin RNA (shRNA), and other short RNAs.

And it all started with Jacob and Monod who established the key concepts of transcriptional control in 1961. Their work and many subsequent studies established that DNA binding transcription factors (trans-factors) occupy specific DNA sequences at control elements (cis-elements). Both, Jacob and Monod received the Nobel Prize in Physiology or Medicine in 1965 jointly with André Lwoff “for their discoveries concerning genetic control of enzyme and virus synthesis”. These transcription factors recruit and regulate the transcription apparatus. Extensive studies in eukaryotic systems have lead to the present-day consensus model of selective gene control and to our increased knowledge of mammalian regulatory elements and the transcriptional and chromatin regulators that operate at these sites.  Furthermore, it is now understood that a small fraction of the hundreds of transcription factors that are present in a cell dominate the control of a large portion of the gene expression program.

The use of oligonucleotide microarrays and advanced sequencing technologies in recent years has allowed for the identification of a large amount of previously unrecognized noncoding RNAs (ncRNAs) in the genomes of many species from budding yeast to man. Cabilli et al. in 2011 estimated that there are approximately 4,000 to 5,000 human lincRNAs. Some of these show sequence conservation at ncRNA exons relative to neighboring neutral sequences. This is now thought to be consistent with functional constrains on at least a proportion of these genes.

Scientists have accumulated plenty of experimental evidence that indicates that many different diseases and syndromes such as cancer, autoimmunity, neurological disorders, diabetes, cardiovascular disease, and obesity, among others, can be caused by mutations in regulatory sequences and in the transcription factors, cofactors, chromatin regulators, and noncoding RNAs (ncRNAs) that interact with them.

These insights have altered our view of the underlying cause for some diseases.  In addition, the human genome project, the GENCODE project, and part of the ENCODE (ENCyclopedia Of DNA Elements) project have already provided and are providing more extensive annotations of genetic features for the entire human genome at a higher accuracy never known before.

The GENCODE gene set is an attempt to catalog noncoding transcription by utilizing a combination of computational analysis, human and mammalian cDNAs/ESTs alignments, and extensive manual curation to validate their noncoding potential. These approaches have already resulted in sets of gene annotations including all protein-coding loci with alternatively transcribed variants, non-coding loci with evidence for transcripts, and the annotation of pseudogenes. The annotation of gene sets is carried out using a mixture of manual annotations, experimental analysis and computational biology methods. The table below lists identified features of the human genome.

Features of Human Genes

Class

Abbreviation

Function

Estimated Number

Messenger RNA

mRNA

protein coding

20,078a

Ribosomal RNA

rRNA

structural and functional component of ribosome

531a

Transfer RNA

tRNA

translational adaptor molecule

512b

Small nuclear RNA

snRNA

processing of pre-mRNA

1,923a

Small nucleolar RNA

snoRNA

processing of rRNA, tRNA, and snRNA

1,529a

Antisense RNA

aRNA

gene regulation

4,424a

Long noncoding RNA

lncRNA

gene regulation

12,933a

MicroRNA

miRNA

translational inhibition and mRNA degradation

>500c

Small interfering RNA

siRNA

posttranscriptional gene silencing

n/ad

Piwi-interacting RNA

piRNA

protect genome integrity

n/ae

Enhancer RNA

eRNA

unknown

variablef

a   GENCODE (Harrow et al., 2012);

b   HGNC database (Seal et al., 2011; http://www.genenames.org);

c   2,000–3,000 putative miRNA have been annotated (Harrow et al., 2012), but the majority are not validated.

d   Human endogenous siRNA are rare and have not been systematically identified;

e   Piwi-interacting RNA (piRNA) have not been systematically identified, although estimates indicate that hundreds of piRNAs are derived from each of more than 100 loci (Aravin et al., 2006; Brennecke et al., 2007; Girard et al., 2006);

f   Enhancer RNAs (eRNAs) are generated from active enhancers, thus the number of eRNAs depends on the set of active enhancers in a cell (Kim et al., 2010; Wang et al., 2011). Current estimates indicate that 25%–80% of active enhancers generate eRNAs.

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Recent improvements made in high-throughput sequencing technologies have tremendously increased our ability to sequence whole genomes which now far exceed the capability of our present available techniques to decipher the information they encode.

Publicly available gene sets such as RefSeq, AceView, and GENCODE are generated by a combination of manual and automated annotation. In addition different methods have been developed to optimize the annotation criteria used.

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Classification of lncRNA

lncRNAs can be classified into the following locus biotypes based on their location with respect to protein-coding genes:

1.  Intergenic lncRNA:  Intergenic lncRNAs are transcribed intergenetically from both strands.

2.  Intronic lncRNA:  Intronic lncRNAs are entirely transcribed from introns of protein-coding genes.

3.    Sense lncRNA:  Sense lncRNAs are transcribed from the sense strand of protein-coding genes and contain exons from protein-coding genes that overlap with part of protein-coding genes or cover the entire sequence of a protein-coding gene through an intron.

4.   Antisense lncRNA:  Antisense lncRNAs are transcribed from the antisense strand of the protein-coding genes that overlap with exonic or intronic regions or cover the entire protein-coding sequence through an intron.

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However, it is prudent to point out that the present classification of lncRNAs is highly dependent on the current existing knowledge. Therefore frequent validation of lncRNA classification systems may be needed as more experimental data become available, when necessary. In addition, lncRNAs can be further divided into different groups based on length distribution as pointed out by Ma et al. in 2013.

Classification based on size.

1.   Small-lncRNAs: 200 to 950 nucleotides long. 58% are found in the human genome.

2.  Medium-lncRNAs: 950 to 4,800 nucleotides long. 78% are found in the mouse genome.

3.  Large non-coding RNAs: >4,800 nucleotides long.

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Further, it needs to be pointed out that presently there is still an uncertainty between comparative results. However, it has become clear that lncRNAs are emerging as regulatory elements of embryonic pluripotency, differentiation, and patterning of the body axis as well as promoting developmental transitions.

Potential Functions and Molecular Mechanisms of lncRNAs

Wang and Chang in 2011 illustrated the construction of complex functions by using combinations of archetypical molecular mechanisms of lncRNAs.

 

lncRNA functions

Schematic diagram of the four archetypes of lncRNA mechanisms

(Adapted from Wang, and Chang, Mol Cell. 2011)

Archetype I:   As Signals, lncRNA expression can faithfully reflect the combinatorial actions of transcription factors (colored ovals) or signaling pathways to indicate gene regulation in space and time.

Archetype II:  As Decoys, lncRNAs can titrate away transcription factors and other proteins away from chromatin, or titrate the protein factors into nuclear subdomains. A further example of decoys is lncRNA decoy for miRNA target sites (not shown on schematic).

Archetype III:  As Guides, lncRNAs can recruit chromatin modifying enzymes to target genes, either in cis (near the site of lncRNA production) or in trans to distant target genes.

Archetype IV:  As scaffolds, lncRNAs can bring together multiple proteins to form ribonucleoprotein complexes. The lncRNA-RNP may act on chromatin as illustrated to affect histone modifications. In other instances, the lncRNA scaffold is structural and stabilizes nuclear structures or signaling complexes”

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References

Chakalova, L., et al., Replication and transcription: shaping the landscape of the genome. Nat Rev Genet, 2005. 6(9): p. 669-77.

Moran N. Cabili, Cole Trapnell, Loyal Goff, et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 2011 25: 1915-1927 originally published online September 2, 2011. Access the most recent version at doi:10.1101/gad.17446611.

Harrow, J., Frankish, A., Gonzalez, J.M., Tapanari, E., Diekhans, M., Kokocinski, F., Aken, B.L., Barrell, D., Zadissa, A., Searle, S., et al. (2012). GENCODE: the reference human genome annotation for The ENCODE

Project. Genome Res. 22, 1760–1774.

He, Y., et al., The antisense transcriptomes of human cells. Science, 2008. 322(5909): p. 1855-7.

Jacob, F., and Monod, J. (1961). Genetic regulatory mechanisms in the synthesis of proteins. J. Mol. Biol. 3, 318–356.

Katayama, S., et al., Antisense transcription in the mammalian transcriptome. Science, 2005. 309(5740): p. 1564-6.

Khalil, A.M., et al., Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A, 2009. 106(28): p. 11667-72.

Tong Ihn Leeand Richard A. Young; Transcriptional Regulation and Its Misregulation in Disease. 2013 Cell 152, 1237-1251.

Ma L, Bajic VB, Zhang Z.; On the classification of long non-coding RNAs. RNA Biol. 2013 Apr 15;10(6), 1-10.

Mercer, T.R., et al., Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci U S A, 2008. 105(2): p. 716-21.

Nakaya, H.I., et al., Genome mapping and expression analyses of human intronic noncoding RNAs reveal tissue-specific patterns and enrichment in genes related to regulation of transcription. Genome Biol, 2007. 8(3): p. R43.

Okada, Y., et al., Comparative expression analysis uncovers novel features of endogenous antisense transcription. Hum Mol Genet, 2008. 17(11): p. 1631-40.

Struhl, K., Transcriptional noise and the fidelity of initiation by RNA polymerase II. Nat Struct Mol Biol, 2007. 14(2): p. 103-5.

Wang KC, Chang HY.; Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011 Sep 16;43(6):904-14. doi: 10.1016/j.molcel.2011.08.018.

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Categories: Artificial Nucleic Acids, Bioanalysis, Bioinformatics, BNA RNA, BNAs, Bridged Nucleic Acids, Cellular Reprogramming, Chromatin, conjugation, Deep sequencing, DNA, DNA Analysis, DNA Editing, DNA Hybridization, DNA Structure, DNA Synthesis, Epigenetics, Genetics, Genome, Hybridization, lncRNA, Long noncoding RNA, Mass spectrometry, Next-generation sequencing, non-coding RNAs, Nucleoprotein, Oligonucleotide Synthesis, Regulatory RNA, RNA, RNA Editing, RNA Structure, RNA Synthesis, Sequence Annotation, Sequencing, short open reading frames (sORF), Synthesis

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  1. RNA FISH can be used to visualize subcellular locations of RNA or RNA-RNB proteincomplexes including the location of noncoding RNAs ! «

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