Identification of <i>cis</i>- and <i>trans</i>-acting factors involved in the localization of MALAT-1 noncoding RNA to nuclear speckles

Miyagawa, Ryu; Tano, Keiko; Mizuno, Risuke; Nakamura, Yoshikazu; Ijiri, Kenichi; Rakwal, Randeep; Shibato, Junko; Masuo, Yoshinori; Mayeda, Akila; Hirose, Tetsuro; Akimitsu, Nobuyoshi

doi:10.1261/rna.028639.111

Cited by 203 publications

(199 citation statements)

References 67 publications

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“…2C). This is consistent with previous reports that indicated that this region is important for targeting endogenous MALAT1 to nuclear speckles (Tripathi et al 2010;Miyagawa et al 2012). …”

Section: Generation Of An Expression Plasmid That Accurately Recapitusupporting

confidence: 94%

A triple helix stabilizes the 3′ ends of long noncoding RNAs that lack poly(A) tails

et al. 2012

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The MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) locus is misregulated in many human cancers and produces an abundant long nuclear-retained noncoding RNA. Despite being transcribed by RNA polymerase II, the 39 end of MALAT1 is produced not by canonical cleavage/polyadenylation but instead by recognition and cleavage of a tRNA-like structure by RNase P. Mature MALAT1 thus lacks a poly(A) tail yet is expressed at a level higher than many protein-coding genes in vivo. Here we show that the 39 ends of MALAT1 and the MEN b long noncoding RNAs are protected from 39-59 exonucleases by highly conserved triple helical structures. Surprisingly, when these structures are placed downstream from an ORF, the transcript is efficiently translated in vivo despite the lack of a poly(A) tail. The triple helix therefore also functions as a translational enhancer, and mutations in this region separate this translation activity from simple effects on RNA stability or transport. We further found that a transcript ending in a triple helix is efficiently repressed by microRNAs in vivo, arguing against a major role for the poly(A) tail in microRNA-mediated silencing. These results provide new insights into how transcripts that lack poly(A) tails are stabilized and regulated and suggest that RNA triple-helical structures likely have key regulatory functions in vivo.

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“…2C). This is consistent with previous reports that indicated that this region is important for targeting endogenous MALAT1 to nuclear speckles (Tripathi et al 2010;Miyagawa et al 2012). …”

Section: Generation Of An Expression Plasmid That Accurately Recapitusupporting

confidence: 94%

A triple helix stabilizes the 3′ ends of long noncoding RNAs that lack poly(A) tails

et al. 2012

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“…Indeed, previous reports stated that nuclear-localized ncRNA such as RN7SK (Robb et al 2005;Berezhna et al 2006), MALAT1 (Tano et al 2010;Miyagawa et al 2012), and NEAT1 (Clemson et al 2009) could be silenced by siRNAs. There are at least two possibilities for silencing nuclear-localized RNA by siRNA: (1) The component of siRNA-induced silencing localized in the nucleus can function to cleave endogenous nuclear target RNAs in the nucleus (Robb et al 2005).…”

Section: Discussionmentioning

confidence: 99%

“…5B; Supplemental Fig. S11; Hutchinson et al 2007;Miyagawa et al 2012). These five SLiTs may localize to specific nuclear domains by forming a dense RNA-protein complex, similar to NEAT1 and MALAT1.…”

Section: Bric-seq Reveals Hundreds Of Slits In Mammalsmentioning

confidence: 99%

Genome-wide determination of RNA stability reveals hundreds of short-lived noncoding transcripts in mammals

Tani¹,

Mizutani²,

Salam³

et al. 2012

Genome Res.

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Mammalian genomes produce huge numbers of noncoding RNAs (ncRNAs). However, the functions of most ncRNAs are unclear, and novel techniques that can distinguish functional ncRNAs are needed. Studies of mRNAs have revealed that the half-life of each mRNA is closely related to its physiological function, raising the possibility that the RNA stability of an ncRNA reflects its function. In this study, we first determined the half-lives of 11,052 mRNAs and 1418 ncRNAs in HeLa Tet-off (TO) cells by developing a novel genome-wide method, which we named 59-bromo-uridine immunoprecipitation chase-deep sequencing analysis (BRIC-seq). This method involved pulse-labeling endogenous RNAs with 59-bromo-uridine and measuring the ongoing decrease in RNA levels over time using multifaceted deep sequencing. By analyzing the relationship between RNA half-lives and functional categories, we found that RNAs with a long half-life (t 1/2 $ 4 h) contained a significant proportion of ncRNAs, as well as mRNAs involved in housekeeping functions, whereas RNAs with a short halflife (t 1/2 < 4 h) included known regulatory ncRNAs and regulatory mRNAs. The stabilities of a significant set of short-lived ncRNAs are regulated by external stimuli, such as retinoic acid treatment. In particular, we identified and characterized several novel long ncRNAs involved in cell proliferation from the group of short-lived ncRNAs. We designated this novel class of ncRNAs with a short half-life as Short-Lived noncoding Transcripts (SLiTs). We propose that the strategy of monitoring RNA half-life will provide a powerful tool for investigating hitherto functionally uncharacterized regulatory RNAs.

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“…Alternatively, NEAT1_1/2 may possess a nuclear retention element within its body, as has been reported for metastasis-associated lung adenocarcinoma transcript 1 (Malat-1) lncRNA. 21 Together, these unusual features in NEAT1 biogenesis cause it to act as "architectural RNA" for paraspeckle formation in the nucleus.…”

Section: Introductionmentioning

confidence: 99%

Paraspeckle formation during the biogenesis of long non-coding RNAs

2013

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Paraspeckles are unique subnuclear structures that are built around a specific long non-coding RNA (lncRNA), NEAT1, which is comprised of two isoforms (NEAT1_1 and NEAT1_2) that are produced by alternative 3'-end processing. NEAT1 lncRNAs are unusual RNA polymerase II transcripts that lack introns. The non-polyadenylated 3'-end of NEAT1_2 is non-canonically processed by RNase P. NEAT1_2 is an essential component for paraspeckle formation. Paraspeckles form during the NEAT1_2 lncRNA biogenesis process, which encompasses transcription from its own chromosome locus through lncRNA processing and accumulation. Recent RNAi analyses of 40 paraspeckle proteins (PSPs) identified four PSPs that are required for paraspeckle formation by mediating NEAT1 processing and accumulation. In particular, HNRNPK was shown to arrest CFIm-dependent NEAT1_1 polyadenylation, leading to NEAT1_2 synthesis. The other three PSPs were required for paraspeckle formation, but did not affect NEAT1_2 expression. This observation suggests that NEAT1_2 accumulation is necessary but not sufficient for paraspeckle formation. An additional step, presumably the bundling of NEAT1 ribonucleoprotein sub-complexes, may be required for construction of the intact paraspeckle structure. NEAT1 expression is likely regulated at transcriptional and post-transcriptional steps under certain stress conditions, suggesting roles for paraspeckles in the lncRNA-mediated regulation of gene expression, such as the nucleocytoplasmic transport of mRNA in response to certain stimuli.

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Identification of cis- and trans-acting factors involved in the localization of MALAT-1 noncoding RNA to nuclear speckles

Cited by 203 publications

References 67 publications

A triple helix stabilizes the 3′ ends of long noncoding RNAs that lack poly(A) tails

A triple helix stabilizes the 3′ ends of long noncoding RNAs that lack poly(A) tails

Genome-wide determination of RNA stability reveals hundreds of short-lived noncoding transcripts in mammals

Paraspeckle formation during the biogenesis of long non-coding RNAs

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