Tipping the balance of RNA stability by 3′ editing of the transcriptome

Chung, Christina Z.; Seidl, Lauren E.; Mann, Mitchell R; Heinemann, Ilka U.

doi:10.1016/j.bbagen.2017.05.003

Cited by 22 publications

(28 citation statements)

References 127 publications

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“…Grin2a, NMDA2A ionotropic glutamate receptor; Sgms1, sphingomyelin synthase 1; Tcf12, transcription factor 12; Homer1, homer scaffolding protein 1; Slc6a6, solute carrier family 6 (neurotransmitter transporter, taurine), member 6; Gars, glycyl-tRNA synthetase; and Rlim, ring finger protein, LIM domain interacting. stability and polyuridylation degradation (Chung et al 2017). The most common pattern in the 5 ′ and seed regions was consistent with ADAR activity, which was responsible for 37.4% of all events.…”

Section: Discussionmentioning

confidence: 57%

Strong conservation of inbred mouse strain microRNA loci but broad variation in brain microRNAs due to RNA editing and isomiR expression

Trontti

Väänänen

Sipilä

et al. 2018

RNA

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Diversity in the structure and expression of microRNAs, important regulators of gene expression, arises from SNPs, duplications followed by divergence, production of isomiRs, and RNA editing. Inbred mouse strains and crosses using them are important reference populations for genetic mapping, and as models of human disease. We determined the nature and extent of interstrain miRNA variation by (i) identifying miRNA SNPs in whole-genome sequence data from 36 strains, and (ii) examining miRNA editing and expression in hippocampus (Hpc) and frontal cortex (FCx) of six strains, to facilitate the study of miRNAs in neurobehavioral phenotypes. miRNA loci were strongly conserved among the 36 strains, but even the highly conserved seed region contained 16 SNPs. In contrast, we identified RNA editing in 58.9% of miRNAs, including 11 consistent editing events in the seed region. We confirmed the functional significance of three conserved edits in the miR-379/410 cluster, demonstrating that edited miRNAs gained novel target mRNAs not recognized by the unedited miRNAs. We found significant interstrain differences in miRNA and isomiR expression: Of 779 miRNAs expressed in Hpc and 719 in FCx, 262 were differentially expressed (190 in Hpc, 126 in FCx, 54 in both). We also identified 32 novel miRNA candidates using miRNA prediction tools. Our studies provide the first comprehensive analysis of SNP, isomiR, and RNA editing variation in miRNA loci across inbred mouse strains, and a detailed catalog of expressed miRNAs in Hpc and FCx in six commonly used strains. These findings will facilitate the molecular analysis of neurological and behavioral phenotypes in this model organism.

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Section: Discussionmentioning

confidence: 57%

Strong conservation of inbred mouse strain microRNA loci but broad variation in brain microRNAs due to RNA editing and isomiR expression

Trontti

Väänänen

Sipilä

et al. 2018

RNA

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“…We further tested the reporter system by assessing miRNA levels in cells depleted for the let-7 degradative enzyme Tut4, which has been shown previously to affect miRNA degradation [ 1 , 29 , 36 , 37 ]. Tut4 polyuridylates let-7 miRNAs, marking them for degradation by the exonuclease Dis3L2 ( Figure 1 b) [ 1 ]. Tut4 was knocked down using siRNA, and partial knockdown of ~50% of Tut4 was confirmed by western blotting ( Figure 2 b).…”

Section: Resultsmentioning

confidence: 99%

“…Human gene expression and RNA transcript stability can be regulated before, during, and after transcription. MicroRNAs (miRNAs) regulate transcript stability by binding to messenger RNAs (mRNAs) in complementary regions, inducing endonuclease-mediated cleavage or inhibiting protein synthesis [ 1 ]. In mammals, miRNAs usually contain sequence homology to their target transcript in their 5′ and 3′ untranslated regions (UTR) [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…Lin28 binds to precursor miRNA (pre-miRNA) let-7 and recruits Tut4, which subsequently polyuridylates the pre-miRNA. Polyuridylated RNAs are degraded by the U-specific exonuclease Dis3L2 [ 1 ]. Screening for small molecule inhibitors of let-7 degradative enzymes currently relies on in vitro biochemical assays to screen for functional inhibition of the respective proteins.…”

Section: Introductionmentioning

confidence: 99%

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MiRAR—miRNA Activity Reporter for Living Cells

Turk

Chung

Manni

et al. 2018

Genes

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microRNA (miRNA) activity and regulation are of increasing interest as new therapeutic targets. Traditional approaches to assess miRNA levels in cells rely on RNA sequencing or quantitative PCR. While useful, these approaches are based on RNA extraction and cannot be applied in real-time to observe miRNA activity with single-cell resolution. We developed a green fluorescence protein (GFP)-based reporter system that allows for a direct, real-time readout of changes in miRNA activity in live cells. The miRNA activity reporter (MiRAR) consists of GFP fused to a 3′ untranslated region containing specific miRNA binding sites, resulting in miRNA activity-dependent GFP expression. Using qPCR, we verified the inverse relationship of GFP fluorescence and miRNA levels. We demonstrated that this novel optogenetic reporter system quantifies cellular levels of the tumor suppressor miRNA let-7 in real-time in single Human embryonic kidney 293 (HEK 293) cells. Our data shows that the MiRAR can be applied to detect changes in miRNA levels upon disruption of miRNA degradation pathways. We further show that the reporter could be adapted to monitor another disease-relevant miRNA, miR-122. With trivial modifications, this approach could be applied across the miRNome for quantification of many specific miRNA in cell cultures, tissues, or transgenic animal models.

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“…110 In humans, uridylation was proposed to decrease the abundance of several miR-NAs. 46,78,111,114,115 Uridylation definitely participates in the destabilization of miRNAs in case of high complementarity to their targets. 50,106,114,[116][117][118] This process is referred to as target RNA-directed miRNA degradation (TDMD).…”

Section: Uridylation and Decay Of Small Rnasmentioning

confidence: 99%

RNA uridylation: a key posttranscriptional modification shaping the coding and noncoding transcriptome

et al. 2017

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RNA uridylation is a potent and widespread posttranscriptional regulator of gene expression. RNA uridylation has been detected in a range of eukaryotes including trypanosomes, animals, plants, and fungi, but with the noticeable exception of budding yeast. Virtually all classes of eukaryotic RNAs can be uridylated and uridylation can also tag viral RNAs. The untemplated addition of a few uridines at the 3 0 end of a transcript can have a decisive impact on RNA's fate. In rare instances, uridylation is an intrinsic step in the maturation of noncoding RNAs like for the U6 spliceosomal RNA or mitochondrial guide RNAs in trypanosomes. Uridylation can also switch specific miRNA precursors from a degradative to a processing mode. This switch depends on the number of uridines added which is regulated by the cellular context. Yet, the typical consequence of uridylation on mature noncoding RNAs or their precursors is to accelerate decay. Importantly, mRNAs are also tagged by uridylation. In fact, the advent of novel high throughput sequencing protocols has recently revealed the pervasiveness of mRNA uridylation, from plants to humans. As for noncoding RNAs, the main function to date for mRNA uridylation is to promote degradation. Yet, additional roles begin to be ascribed to U-tailing such as the control of mRNA deadenylation, translation control and possibly storage. All these new findings illustrate that we are just beginning to appreciate the diversity of roles played by RNA uridylation and its full temporal and spatial implication in regulating gene expression.

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Tipping the balance of RNA stability by 3′ editing of the transcriptome

Cited by 22 publications

References 127 publications

Strong conservation of inbred mouse strain microRNA loci but broad variation in brain microRNAs due to RNA editing and isomiR expression

Strong conservation of inbred mouse strain microRNA loci but broad variation in brain microRNAs due to RNA editing and isomiR expression

MiRAR—miRNA Activity Reporter for Living Cells

RNA uridylation: a key posttranscriptional modification shaping the coding and noncoding transcriptome

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