Malat1 is not an essential component of nuclear speckles in mice

Nakagawa, Shinichi; Ip, Joanna Y.; Shioi, Go; Tripathi, Vidisha; Zong, Xinying; Hirose, Tetsuro; Prasanth, Kannanganattu V.

doi:10.1261/rna.033217.112

Cited by 302 publications

(315 citation statements)

References 40 publications

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“…It is important to note, however, that this approach cannot ascribe any observed biological activity to a functional lncRNA transcript, particularly in the absence of rescue experiments. Other in vivo loss-of-function approaches have also been applied to address the question of lncRNA functional roles (11,(44)(45)(46)(47)(48). However, it is important to stress that no single method exists that can account for all possible mechanisms of action of a noncoding locus (49).…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain

Goff

Groff

Sauvageau

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

151

131

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Long noncoding RNAs (lncRNAs) have been implicated in numerous cellular processes including brain development. However, the in vivo expression dynamics and molecular pathways regulated by these loci are not well understood. Here, we leveraged a cohort of 13 lncRNAnull mutant mouse models to investigate the spatiotemporal expression of lncRNAs in the developing and adult brain and the transcriptome alterations resulting from the loss of these lncRNA loci. We show that several lncRNAs are differentially expressed both in time and space, with some presenting highly restricted expression in only selected brain regions. We further demonstrate altered regulation of genes for a large variety of cellular pathways and processes upon deletion of the lncRNA loci. Finally, we found that 4 of the 13 lncRNAs significantly affect the expression of several neighboring proteincoding genes in a cis-like manner. By providing insight into the endogenous expression patterns and the transcriptional perturbations caused by deletion of the lncRNA locus in the developing and postnatal mammalian brain, these data provide a resource to facilitate future examination of the specific functional relevance of these genes in neural development, brain function, and disease.T he exquisite complexity of the mammalian brain derives from its vast diversity of neuronal and glial cell types (1, 2). The specification and differentiation of such a variety of cell types during brain development is finely orchestrated spatiotemporally by the regulation of complex transcriptional programs. Increasing evidence points to a role for long noncoding RNAs (lncRNAs) as key regulatory elements of this process. Intriguingly, within the mammalian body, the largest repertoire and diversity of lncRNA genes outside the germ line occurs in the brain (3-10), where lncRNAs exhibit regional and cell-specific localization (6, 10). Although many unanswered questions remain regarding the functional activity and molecular mechanisms of lncRNA loci, the expression patterns of lncRNAs may serve as a proxy signal for important, context-specific biological activity.A role for lncRNA genes in brain development and function is supported by the fact that ablation of two lncRNA loci, Evf2 and Pantr2 (linc-Brn1b), perturbs neuronal development (11, 12). Loss of Evf2, a developmentally regulated lncRNA that controls transcriptional activity through cooperation with the homeodomain protein DLX-2 (11), leads to abnormal development and synaptic function of hippocampal GABAergic interneurons (11). Similarly, ablation of the Pantr2 locus results in a decreased number of intermediate progenitors in the developing telencephalon, reduced neurons in L2/3 of the cerebral cortex, and disorganization of the barrel cortex (12). Furthermore, human genetic studies have pointed to lncRNAs as potential factors in brain disorders (10,(13)(14)(15)(16).To gain preliminary insights into the functional and physiological relevance of lncRNA loci in vivo, we previously generated knockout (KO) mouse models of ...

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Section: Discussionmentioning

confidence: 99%

Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain

Goff

Groff

Sauvageau

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

151

131

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“…A most puzzling fact, however, is that in spite of their abundance and association with some of the most prominent subnuclear structures, knockouts of neither NEAT1 nor MALAT1 have robust phenotypes (Nakagawa et al , 2012Eissmann et al 2012;Zhang et al 2012). These recent observations add to the mystery surrounding lncRNAs and support the assertion that quantity and function do not necessarily correlate.…”

Section: Mechanisms Of Action: Finding Pattern In Chaosmentioning

confidence: 97%

Long Noncoding RNAs: Past, Present, and Future

2013

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Long noncoding RNAs (lncRNAs) have gained widespread attention in recent years as a potentially new and crucial layer of biological regulation. lncRNAs of all kinds have been implicated in a range of developmental processes and diseases, but knowledge of the mechanisms by which they act is still surprisingly limited, and claims that almost the entirety of the mammalian genome is transcribed into functional noncoding transcripts remain controversial. At the same time, a small number of well-studied lncRNAs have given us important clues about the biology of these molecules, and a few key functional and mechanistic themes have begun to emerge, although the robustness of these models and classification schemes remains to be seen. Here, we review the current state of knowledge of the lncRNA field, discussing what is known about the genomic contexts, biological functions, and mechanisms of action of lncRNAs. We also reflect on how the recent interest in lncRNAs is deeply rooted in biology's longstanding concern with the evolution and function of genomes.T HE past several years have witnessed a steep rise of interest in the study of lncRNAs. Almost on a weekly basis, it seems that a new lncRNA is found to be up-or downregulated in a particular disease, or a new class of noncoding transcripts is uncovered by a transcriptomic study, or a new article heralds a paradigm shift that lncRNAs will bring to our understanding of biology. Without a doubt, the advent of sensitive, high-throughput genomic technologies such as microarrays and next-generation sequencing (NGS) has resulted in an unprecedented ability to detect novel transcripts, the vast majority of which seem not to be derived from annotated protein-coding genes. Despite this explosion of data, however, surprisingly little is known about how lncRNAs function, how many different types of lncRNAs exist, or even whether most of them carry biological significance.In this review, we focus on recently discovered lncRNAs of .200 nt, place these new discoveries in historical context, and outline areas where additional work is needed. The review does not cover "classic" ncRNAs such as ribosomal (r) RNAs, ribozymes, transfer (t)RNAs, small nuclear (sn)RNAs, small nucleolar (sno)RNAs, and telomere-associated RNAs (TERC, TERRA); nor does it cover small ncRNAs such as microRNAs (miRNAs), endogenous small interfering (endo-si)RNAs that participate in RNA interference (RNAi), and Piwi-associated (pi)RNAs. We refer readers to the many

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“…The long MALAT1 transcript is retained in the nucleus in nuclear speckles (Hutchinson et al 2007), where it has been proposed to regulate alternative splicing (Tripathi et al 2010), transcriptional activation (Yang et al 2011b), and the expression of nearby genes in cis (Nakagawa et al 2012;Zhang et al 2012). Although the MALAT1 locus appears to be dispensable for mouse development (Eissmann et al 2012;Nakagawa et al 2012;Zhang et al 2012), MALAT1 is overexpressed in many human cancers (Ji et al 2003;Lin et al 2007;Lai et al 2011), suggesting that it may have an important function during cancer progression.…”

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confidence: 99%

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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Malat1 is not an essential component of nuclear speckles in mice

Cited by 302 publications

References 40 publications

Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain

Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain

Long Noncoding RNAs: Past, Present, and Future

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

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