The Nuclear-Retained Noncoding RNA MALAT1 Regulates Alternative Splicing by Modulating SR Splicing Factor Phosphorylation

Tripathi, Vidisha; Ellis, Jonathan D.; Shen, Zhen; Song, David; Pan, Qun; Watt, Andrew T.; Freier, Susan M.; Bennett, C. Frank; Sharma, Alok; Bubulya, Paula A.; Blencowe, Benjamin J.; Prasanth, Supriya G.; Prasanth, Kannanganattu V.

doi:10.1016/j.molcel.2010.08.011

Cited by 1,947 publications

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“…They contain transcription factors, 3 0 -end RNA processing factors, translation regulation factors and the large subunit of RNA polymerase II. 28,29 Jia et al have shown also that the inhibition of transcription changes the nucleoplasmic distribution of FTO, which becomes more concentrated at speckles. Of note, we observed different pattern of nucleoplasmic FTO staining in cells with different proliferation rates.…”

Section: Discussionmentioning

confidence: 99%

FTO levels affect RNA modification and the transcriptome

et al. 2012

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A block of single-nucleotide polymorphisms within intron 1 of the FTO (fat mass and obesity associated) gene is associated with variation in body weight. Previous works suggest that increased expression of FTO, which encodes a 2-oxoglutaratedependent nucleic acid demethylase, leads to increased body weight, although the underlying mechanism has remained unclear. To elucidate the function of FTO, we examined the consequences of altered FTO levels in cultured cells and murine brain. Here we show that a knockdown of FTO in HEK293 cells affects the transcripts levels of genes involved in the response to starvation, whereas overexpression of FTO affects the transcript levels of genes related to RNA processing and metabolism. Subcellular localization of FTO further strengthens the latter notion. Using immunocytochemistry and confocal laser scanning microscopy, we detected FTO in nuclear speckles and -to a lesser and varying extent -in the nucleoplasm and nucleoli of HEK293, HeLa and MCF-7 cells. Moreover, RNA modification analyses revealed that loss of Fto affects the 3-methyluridine/ uridine and pseudouridine/uridine ratios in total brain RNA. We conclude that altered levels of FTO have multiple and diverse consequences on RNA modifications and the transcriptome. Keywords: FTO; RNA modifications; nuclear speckles; transcriptome INTRODUCTION Genome-wide association studies have revealed a strong association between a block of single-nucleotide polymorphisms (SNPs) in intron 1 of the fat mass and obesity-associated (FTO) gene, body mass index and other obesity-related traits in children and adults of different populations. 1-3 Stratigopoulos et al 4 have suggested that one of the SNPs (rs8050136) affects binding of the transcriptional regulator CUX1. By studying allelic expression levels in heterozygous individuals, we have found that the risk allele of the FTO gene makes more transcripts and have proposed that increased expression of the FTO gene leads to increased body weight. 5 This hypothesis is supported by the clinical findings in rare patients and in mouse models with an FTO/Fto mutation. Homozygous loss-of-function of FTO was reported to cause severe growth retardation and multiple malformations, 6 whereas a duplication of FTO was found to be associated with morbid obesity. 7 Fto-knockout mice 8 and mice with a missense mutation in exon 6 9 showed leanness, postnatal growth retardation and a higher metabolic rate. Mice with one or two additional copies of Fto had a gene-dosage-dependent increase in body weight. 10 FTO is a member of non-heme Fe(II)-and a-ketoglutaratedependent oxygenase superfamily and is found in vertebrates and green algea, but not in invertebrate animals, fungi and green plants. 11 By in vitro studies, FTO was shown to function as a demethylase with a strong preference for 3meU and 3meT in single-stranded RNA and DNA, respectively. 12,13 Han et al 14 have provided structural evidence for understanding the substrate specificity of FTO and have suggested

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Section: Discussionmentioning

confidence: 99%

FTO levels affect RNA modification and the transcriptome

et al. 2012

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“…The fact that the abundant, nuclear-retained, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1; a.k.a. Neat2) is highly conserved in mammals and localized to nuclear speckles led the Prasanth laboratory to investigate the involvement of this non-coding (nc) RNA in pre-mRNA metabolism (54). They found that MALAT1 does not play a role in the formation and maintenance of nuclear speckles but instead, it interacts with a sub-set of SR proteins modulating their sub-nuclear distribution and even more intriguingly, influencing the cellular levels and the ratio of phosphorylated versus de-phosphorylated SR proteins.…”

Section: Post-translational Modifications Of Sr Proteins: Above and Bmentioning

confidence: 99%

Regulating the regulators: Serine/arginine‐rich proteins under scrutiny

et al. 2012

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SummarySerine/arginine-rich (SR) proteins are among the most studied splicing regulators. They constitute a family of evolutionarily conserved proteins that, apart from their initially identified and deeply studied role in splicing regulation, have been implicated in genome stability, chromatin binding, transcription elongation, mRNA stability, mRNA export and mRNA translation. Remarkably, this list of SR protein activities seems far from complete, as unexpected functions keep being unraveled. An intriguing aspect that awaits further investigation is how the multiple tasks of SR proteins are concertedly regulated within mammalian cells. In this article, we first discuss recent findings regarding the regulation of SR protein expression, activity and accessibility. We dive into recent studies describing SR protein auto-regulatory feedback loops involving different molecular mechanisms such as unproductive splicing, microRNA-mediated regulation and translational repression. In addition, we take into account another step of regulation of SR proteins, presenting new findings about a variety of post-translational modifications by proteomics approaches and how some of these modifications can regulate SR protein sub-cellular localization or stability. Towards the end, we focus in two recently revealed functions of SR proteins beyond mRNA biogenesis and metabolism, the regulation of micro-RNA processing and the regulation of small ubiquitin-like modifier (SUMO) conjugation.

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“…Dual RNA FISH and immunofluorescence using probes against MALAT1, U2‐snRNA, and antibodies against SR splicing factor, SRSF1, have been used to clarify the role of MALAT1 in RNA splicing. MALAT 1 was shown to be co‐localized to nuclear speckles with SR splicing factors 48.…”

Section: Methods Used To Localize Lncrnas Inside the Cellmentioning

confidence: 99%

State of the art technologies to explore long non‐coding RNAs in cancer

Salehi

Taheri

Azarpira

et al. 2017

J Cellular Molecular Medi

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Long non‐coding RNAs (lncRNAs) comprise a vast repertoire of RNAs playing a wide variety of crucial roles in tissue physiology in a cell‐specific manner. Despite being engaged in myriads of regulatory mechanisms, many lncRNAs have still remained to be assigned any functions. A constellation of experimental techniques including single‐molecule RNA in situ hybridization (sm‐RNA FISH), cross‐linking and immunoprecipitation (CLIP), RNA interference (RNAi), Clustered regularly interspaced short palindromic repeats (CRISPR) and so forth has been employed to shed light on lncRNA cellular localization, structure, interaction networks and functions. Here, we review these and other experimental approaches in common use for identification and characterization of lncRNAs, particularly those involved in different types of cancer, with focus on merits and demerits of each technique.

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The Nuclear-Retained Noncoding RNA MALAT1 Regulates Alternative Splicing by Modulating SR Splicing Factor Phosphorylation

Cited by 1,947 publications

References 63 publications

FTO levels affect RNA modification and the transcriptome

FTO levels affect RNA modification and the transcriptome

Regulating the regulators: Serine/arginine‐rich proteins under scrutiny

State of the art technologies to explore long non‐coding RNAs in cancer

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