The Dimensions, Dynamics, and Relevance of the Mammalian Noncoding Transcriptome

Deveson, Ira W.; Hardwick, Simon A.; Mercer, Tim R.; Mattick, John S.

doi:10.1016/j.tig.2017.04.004

Cited by 179 publications

(170 citation statements)

References 121 publications

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“…Historically, clinical RNA profiling studies have been small, and have relied on DNA microarrays biased towards the 3’ end of protein-coding transcripts (21–23), resulting in a lack of a consistent global molecular narrative for IS in skeletal muscle. This lack of clarity reflects technical caveats, such as concurrent drug-treatment (for T2DM patients), inadequate consideration of clinical phenotype (23,24), as well as incomplete capture of the transcriptome (25) – and limited statistical power (26). More modern transcriptomic techniques, such as short-read RNA sequencing (RNA-seq) and full transcript ‘tiling-type’ microarrays (27) attempt to provide a complete and accurate view of the transcriptome.…”

Section: Introductionmentioning

confidence: 99%

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A coding and non-coding transcriptomic perspective on the genomics of human metabolic disease

Timmons

Atherton

Larsson

et al. 2018

Nucleic Acids Research

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Genome-wide association studies (GWAS), relying on hundreds of thousands of individuals, have revealed >200 genomic loci linked to metabolic disease (MD). Loss of insulin sensitivity (IS) is a key component of MD and we hypothesized that discovery of a robust IS transcriptome would help reveal the underlying genomic structure of MD. Using 1,012 human skeletal muscle samples, detailed physiology and a tissue-optimized approach for the quantification of coding (>18,000) and non-coding (>15,000) RNA (ncRNA), we identified 332 fasting IS-related genes (CORE-IS). Over 200 had a proven role in the biochemistry of insulin and/or metabolism or were located at GWAS MD loci. Over 50% of the CORE-IS genes responded to clinical treatment; 16 quantitatively tracking changes in IS across four independent studies (P = 0.0000053: negatively: AGL, G0S2, KPNA2, PGM2, RND3 and TSPAN9 and positively: ALDH6A1, DHTKD1, ECHDC3, MCCC1, OARD1, PCYT2, PRRX1, SGCG, SLC43A1 and SMIM8). A network of ncRNA positively related to IS and interacted with RNA coding for viral response proteins (P < 1 × 10−48), while reduced amino acid catabolic gene expression occurred without a change in expression of oxidative-phosphorylation genes. We illustrate that combining in-depth physiological phenotyping with robust RNA profiling methods, identifies molecular networks which are highly consistent with the genetics and biochemistry of human metabolic disease.

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Section: Introductionmentioning

confidence: 99%

“…This characteristic of the DNA library can also invalidate subsequent pathway analysis (33). In addition, RNA-seq profiles of individual tissues (25,30,34,35) do not include the majority of long non-coding RNAs (lncRNAs) and thus to date at least 50% of the tissue transcriptome remains unexplored in most clinical cohorts.…”

Section: Introductionmentioning

confidence: 99%

A coding and non-coding transcriptomic perspective on the genomics of human metabolic disease

Timmons

Atherton

Larsson

et al. 2018

Nucleic Acids Research

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“…The functional significance of resulting lncRNA molecules is actively debated even though biological roles are identified for an increasing number of examples [2][3][4] . Expression of lncRNAs is remarkably specific to the environmental condition, tissue or cell type, arguing for roles of lncRNA in regulation [5][6][7] . In addition to functions carried out by lncRNA molecules, the process of transcribing non-coding DNA sequences can by itself be regulatory in many systems 8,9 .…”

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confidence: 99%

Transcriptional read-through of the long non-coding RNA SVALKA governs plant cold acclimation

Kindgren

Ard

Ivanov

2018

Preprint

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SummaryMost DNA in the genomes of higher organisms does not encode proteins, but is transcribed by RNA polymerase II (RNAPII) into long non-coding RNA (lncRNA). The biological significance of most lncRNA is largely unclear. Here, we identify a lncRNA (SVALKA) in a cold-sensitive region of the Arabidopsis genome. Mutations in SVALKA affect the timing of maximal CBF1 expression and freezing tolerance. RNAPII read-through transcription of SVALKA results in a cryptic lncRNA overlapping CBF1 on the antisense strand, termed asCBF1. asCBF1 transcription is anti-correlated with CBF1 expression. Our molecular dissection reveals that CBF1 is suppressed by RNAPII collision stemming from the SVALKA-asCBF1 lncRNA cascade. The SVK-asCBF1 cascade provides a mechanism to tightly control CBF1 expression and timing that could be exploited to maximize freezing tolerance with mitigated fitness costs. Inversion of the transcriptional direction of a lncRNA cascade relative to the genes in a co-regulated cluster provides an elegant inbuilt negative feedback for cluster expression. Our results provide a compelling example of local gene regulation by lncRNA transcription having a profound impact on the ability of plants to appropriately acclimate to suboptimal environmental conditions. not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/287946 doi: bioRxiv preprint first posted online Mar. 23, 2018; Main RNA Polymerase II (RNAPII) transcription in genomes results in the production of many long noncoding RNAs (lncRNAs) 1 . The functional significance of resulting lncRNA molecules is actively debated even though biological roles are identified for an increasing number of examples [2][3][4] . Expression of lncRNAs is remarkably specific to the environmental condition, tissue or cell type, arguing for roles of lncRNA in regulation [5][6][7] . In addition to functions carried out by lncRNA molecules, the process of transcribing non-coding DNA sequences can by itself be regulatory in many systems 8,9 . Non-coding DNA regions in genomes can therefore affect gene expression by different mechanisms that need to be resolved experimentally.Sessile organisms respond to changing environmental conditions with regulation of gene expression. Early events in the Arabidopsis cold response include rapid transcriptional upregulation of the intron-less C-repeat/dehydration-responsive element binding factors (CBFs) 10,11 . The CBFs are highly conserved transcription factors that promote cold tolerance in many plant species and are often arranged in a single cluster 12. CBF expression during cold exposure activates downstream COLD REGULATED (COR) genes that promote freezing tolerance by adjusting the physiological and biochemical properties of plant cell interiors [13][14][15] . Intriguingly, constitutive CBF expression increases cold-tolerance but is also associated with fitness penalties [16][17][18][19] . antisense CBF1 lncRNA (...

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“…However, this simple model of RNA as a relatively passive carrier of genetic information from DNA to protein has been overturned 1 . In particular, we now know that much of extragenic DNA is transcribed into noncoding RNAs (ncRNAs) and that multiple transcripts, both coding and noncoding, are produced, the latter in both directions, from the same genes 2,3 . Long and short ncRNAs regulate gene expression at almost every step.…”

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confidence: 99%

Tapping the RNA world for therapeutics

Lieberman

2018

Nat Struct Mol Biol

163

127

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A recent revolution in RNA biology has led to the identification of new RNA classes with unanticipated functions, new types of RNA modifications, an unexpected multiplicity of alternative transcripts and widespread transcription of extragenic regions. This development in basic RNA biology has spawned a corresponding revolution in RNA-based strategies to generate new types of therapeutics. Here, I review RNA-based drug design and discuss barriers to broader applications and possible ways to overcome them. Because they target nucleic acids rather than proteins, RNA-based drugs promise to greatly extend the domain of ‘druggable’ targets beyond what can be achieved with small molecules and biologics.

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The Dimensions, Dynamics, and Relevance of the Mammalian Noncoding Transcriptome

Cited by 179 publications

References 121 publications

A coding and non-coding transcriptomic perspective on the genomics of human metabolic disease

A coding and non-coding transcriptomic perspective on the genomics of human metabolic disease

Transcriptional read-through of the long non-coding RNA SVALKA governs plant cold acclimation

Tapping the RNA world for therapeutics

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