Dynamic RNA Modifications in Gene Expression Regulation

doi:10.1016/J.CELL.2017.05.045

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Dynamic RNA Modifications in Gene Expression Regulation

Journal Article•DOI•

Dynamic RNA Modifications in Gene Expression Regulation

Ian A Roundtree¹, Molly E. Evans¹, Tao Pan¹, Chuan He¹, Chuan He² - Show less +1 more•Institutions (2)

University of Chicago¹, Howard Hughes Medical Institute²

15 Jun 2017-Cell (Cell Press)-Vol. 169, Iss: 7, pp 1187-1200

TL;DR: Roles for mRNA modification in nearly every aspect of the mRNA life cycle, as well as in various cellular, developmental, and disease processes are revealed.

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About: This article is published in Cell.The article was published on 2017-06-15 and is currently open access. It has received 1855 citations till now. The article focuses on the topics: MRNA modification & MRNA methylation.

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Journal Article•DOI•

Recognition of RNA N 6 -methyladenosine by IGF2BP proteins enhances mRNA stability and translation

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Huilin Huang¹, Huilin Huang², Hengyou Weng¹, Hengyou Weng², Wen-Ju Sun³, Xi Qin², Xi Qin¹, Hailing Shi⁴, Hailing Shi⁵, Huizhe Wu⁶, Huizhe Wu², Huizhe Wu¹, Boxuan Simen Zhao⁵, Boxuan Simen Zhao⁴, Ana Mesquita², Chang Liu⁴, Chang Liu⁵, Celvie L. Yuan⁷, Yueh-Chiang Hu⁷, Stefan Hüttelmaier⁸, Jennifer R. Skibbe², Rui Su², Rui Su¹, Xiaolan Deng¹, Xiaolan Deng⁶, Xiaolan Deng², Lei Dong¹, Lei Dong², Miao Sun⁷, Chenying Li¹, Chenying Li⁹, Chenying Li², Sigrid Nachtergaele⁵, Sigrid Nachtergaele⁴, Yungui Wang⁹, Yungui Wang², Chao Hu², Chao Hu⁹, Kyle Ferchen², Kenneth D. Greis², Xi Jiang², Xi Jiang¹, Minjie Wei⁶, Liang-Hu Qu³, Jun-Lin Guan², Chuan He⁴, Chuan He⁵, Jian-Hua Yang³, Jianjun Chen², Jianjun Chen¹ - Show less +46 more•Institutions (9)

City of Hope National Medical Center¹, University of Cincinnati Academic Health Center², Sun Yat-sen University³, University of Chicago⁴, Howard Hughes Medical Institute⁵, China Medical University (PRC)⁶, Cincinnati Children's Hospital Medical Center⁷, Martin Luther University of Halle-Wittenberg⁸, Zhejiang University⁹

23 Feb 2018-Nature Cell Biology

TL;DR: This work reports the insulin-like growth factor 2 mRNA-binding proteins as a distinct family of m6A readers that target thousands of mRNA transcripts through recognizing the consensus GG(m6A)C sequence, and identifies IGF2BPs as an additional class of N6-methyladenosine (m 6A) reader proteins.

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Abstract: N6-methyladenosine (m6A) is the most prevalent modification in eukaryotic messenger RNAs (mRNAs) and is interpreted by its readers, such as YTH domain-containing proteins, to regulate mRNA fate. Here, we report the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; including IGF2BP1/2/3) as a distinct family of m6A readers that target thousands of mRNA transcripts through recognizing the consensus GG(m6A)C sequence. In contrast to the mRNA-decay-promoting function of YTH domain-containing family protein 2, IGF2BPs promote the stability and storage of their target mRNAs (for example, MYC) in an m6A-dependent manner under normal and stress conditions and therefore affect gene expression output. Moreover, the K homology domains of IGF2BPs are required for their recognition of m6A and are critical for their oncogenic functions. Thus, our work reveals a different facet of the m6A-reading process that promotes mRNA stability and translation, and highlights the functional importance of IGF2BPs as m6A readers in post-transcriptional gene regulation and cancer biology.

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1,373 citations

Journal Article•DOI•

Non-coding RNA networks in cancer.

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Eleni Anastasiadou¹, Leni S. Jacob¹, Frank J. Slack¹•Institutions (1)

Beth Israel Deaconess Medical Center¹

01 Jan 2018-Nature Reviews Cancer

TL;DR: A deeper understanding of the complex networks of interactions that ncRNAs coordinate would provide a unique opportunity to design better therapeutic interventions.

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Abstract: Thousands of unique non-coding RNA (ncRNA) sequences exist within cells. Work from the past decade has altered our perception of ncRNAs from 'junk' transcriptional products to functional regulatory molecules that mediate cellular processes including chromatin remodelling, transcription, post-transcriptional modifications and signal transduction. The networks in which ncRNAs engage can influence numerous molecular targets to drive specific cell biological responses and fates. Consequently, ncRNAs act as key regulators of physiological programmes in developmental and disease contexts. Particularly relevant in cancer, ncRNAs have been identified as oncogenic drivers and tumour suppressors in every major cancer type. Thus, a deeper understanding of the complex networks of interactions that ncRNAs coordinate would provide a unique opportunity to design better therapeutic interventions.

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1,180 citations

Journal Article•DOI•

Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms.

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Xi Jin¹, Jiangshan Lian¹, Jianhua Hu¹, Jianguo Gao¹, Lin Zheng¹, Yimin Zhang¹, Shaorui Hao¹, Hongyu Jia¹, Huan Cai¹, Xiaoli Zhang¹, Guodong Yu¹, Kaijin Xu¹, Xiaoyan Wang¹, Jueqing Gu¹, Shanyan Zhang¹, Chanyuan Ye¹, Ciliang Jin¹, Yingfeng Lu¹, Xia Yu¹, Xiaopeng Yu¹, Jianrong Huang¹, Kangli Xu¹, Qin Ni¹, Chengbo Yu¹, Biao Zhu¹, Yongtao Li¹, Jun Liu¹, Hong Zhao¹, Xuan Zhang¹, Liang Yu¹, Yongzheng Guo¹, Junwei Su¹, Jingjing Tao¹, Guanjing Lang¹, Xiaoxin Wu¹, Wenrui Wu¹, Ting-Ting Qv¹, Dairong Xiang¹, Ping Yi¹, Ding Shi¹, Yanfei Chen¹, Yue Ren¹, Yunqing Qiu¹, Lanjuan Li¹, Jifang Sheng¹, Yida Yang¹ - Show less +42 more•Institutions (1)

Zhejiang University¹

25 Mar 2020-Gut

TL;DR: Attention to patients with COVID-19 with non-classic symptoms should increase to protect health providers, and sequence mutation of SARS-CoV-2 with m6A methylation and changed binding capacity with ACE2 was showed.

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Abstract: Objective The SARS-CoV-2-infected disease (COVID-19) outbreak is a major threat to human beings. Previous studies mainly focused on Wuhan and typical symptoms. We analysed 74 confirmed COVID-19 cases with GI symptoms in the Zhejiang province to determine epidemiological, clinical and virological characteristics. Design COVID-19 hospital patients were admitted in the Zhejiang province from 17 January 2020 to 8 February 2020. Epidemiological, demographic, clinical, laboratory, management and outcome data of patients with GI symptoms were analysed using multivariate analysis for risk of severe/critical type. Bioinformatics were used to analyse features of SARS-CoV-2 from Zhejiang province. Results Among enrolled 651 patients, 74 (11.4%) presented with at least one GI symptom (nausea, vomiting or diarrhoea), average age of 46.14 years, 4-day incubation period and 10.8% had pre-existing liver disease. Of patients with COVID-19 with GI symptoms, 17 (22.97%) and 23 (31.08%) had severe/critical types and family clustering, respectively, significantly higher than those without GI symptoms, 47 (8.14%) and 118 (20.45%). Of patients with COVID-19 with GI symptoms, 29 (39.19%), 23 (31.08%), 8 (10.81%) and 16 (21.62%) had significantly higher rates of fever >38.5°C, fatigue, shortness of breath and headache, respectively. Low-dose glucocorticoids and antibiotics were administered to 14.86% and 41.89% of patients, respectively. Sputum production and increased lactate dehydrogenase/glucose levels were risk factors for severe/critical type. Bioinformatics showed sequence mutation of SARS-CoV-2 with m6A methylation and changed binding capacity with ACE2. Conclusion We report COVID-19 cases with GI symptoms with novel features outside Wuhan. Attention to patients with COVID-19 with non-classic symptoms should increase to protect health providers.

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1,032 citations

Journal Article•DOI•

Where, When, and How: Context-Dependent Functions of RNA Methylation Writers, Readers, and Erasers

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Hailing Shi¹, Hailing Shi², Jiangbo Wei², Jiangbo Wei¹, Chuan He², Chuan He¹ - Show less +2 more•Institutions (2)

Howard Hughes Medical Institute¹, University of Chicago²

16 May 2019-Molecular Cell

TL;DR: This review highlights recent progress in understanding the function of N6-methyladenosine (m6A), the most abundant internal mark on eukaryotic mRNA, in light of the specific biological contexts of m6A effectors, and emphasizes the importance of context for RNA modification regulation and function.

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909 citations

Journal Article•DOI•

Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism.

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Ying Yang¹, Phillip J. Hsu², Yu-Sheng Chen¹, Yu-Sheng Chen³, Yun-Gui Yang³, Yun-Gui Yang¹ - Show less +2 more•Institutions (3)

Beijing Institute of Genomics¹, Howard Hughes Medical Institute², Chinese Academy of Sciences³

22 May 2018-Cell Research

TL;DR: The current understanding of the m6A modification, particularly the functions of its writers, erasers, readers in RNA metabolism, is described, with an emphasis on its role in regulating the isoform dosage of mRNAs.

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Abstract: N6-methyladenosine (m6A) is a chemical modification present in multiple RNA species, being most abundant in mRNAs. Studies on enzymes or factors that catalyze, recognize, and remove m6A have revealed its comprehensive roles in almost every aspect of mRNA metabolism, as well as in a variety of physiological processes. This review describes the current understanding of the m6A modification, particularly the functions of its writers, erasers, readers in RNA metabolism, with an emphasis on its role in regulating the isoform dosage of mRNAs.

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829 citations

Cites background from "Dynamic RNA Modifications in Gene E..."

...FUNCTIONS IN RNA METABOLISM Recent accumulative studies revealed that m(6)A methylation regulates almost every aspect of mRNA metabolism, from expression and pre-mRNA processing in the nucleus to translation and mRNA decay in the cytoplasm.(1,3,4,10,118) m(6)A has been reported to be associated with alternative polyadenylation (APA),(119,120) which is coupled to the splicing of the last intron....
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...M(6)A READERS Chemical modifications can directly affect properties of RNA transcripts, including charge, base-pairing, secondary structure, and protein-RNA interactions, which in turn shape gene expression by modulating RNA processing, localization, translation, and eventually, decay.(1,3,4,99) Prominently, m(6)A also indirectly affects RNA processing by recruiting specific reader proteins....
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References

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Journal Article•DOI•

IDH1 and IDH2 Mutations in Gliomas

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Hai Yan¹, D. Williams Parsons, Genglin Jin¹, Roger E. McLendon¹, B.K. Ahmed Rasheed¹, Weishi Yuan², Ivan Kos¹, Ines Batinic-Haberle¹, Siân Jones³, Gregory J. Riggins, Henry S. Friedman¹, Allan H. Friedman¹, David A. Reardon¹, James E. Herndon¹, Kenneth W. Kinzler, Victor E. Velculescu, Bert Vogelstein, Darell D. Bigner¹ - Show less +14 more•Institutions (3)

Duke University¹, Food and Drug Administration², Johns Hopkins University³

19 Feb 2009-The New England Journal of Medicine

TL;DR: Mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.

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Abstract: Background A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). Methods We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. Results We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations h...

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4,853 citations

"Dynamic RNA Modifications in Gene E..." refers background in this paper

...2-hydroxyglutarate (2HG), whichmay inhibit FTO and/or ALKBH5 and lead to observed benign outcomes (Brat et al., 2015; Chou et al., 2011; Eckel-Passow et al., 2015; Patel et al., 2012; Yan et al., 2009)....
[...]

Journal Article•DOI•

A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity

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Timothy M. Frayling, Nicholas J. Timpson¹, Michael N. Weedon, Eleftheria Zeggini², Eleftheria Zeggini³, Eleftheria Zeggini⁴, Rachel M. Freathy, Cecilia M. Lindgren, John R. B. Perry, Katherine S. Elliott³, Katherine S. Elliott⁴, Hana Lango, Nigel W. Rayner², Nigel W. Rayner⁴, Nigel W. Rayner³, Beverley M. Shields, Lorna W. Harries, Jeffrey C. Barrett⁴, Jeffrey C. Barrett³, Sian Ellard⁵, Christopher J. Groves², Christopher J. Groves⁴, Bridget A. Knight, Ann-Marie Patch⁵, Andy R Ness¹, Shah Ebrahim⁶, Debbie A Lawlor¹, Susan M. Ring¹, Yoav Ben-Shlomo¹, Marjo-Riitta Järvelin⁷, Marjo-Riitta Järvelin⁸, Ulla Sovio⁷, Ulla Sovio⁸, Amanda J. Bennett², Amanda J. Bennett⁴, David Melzer, Luigi Ferrucci⁹, Ruth J. F. Loos¹⁰, Inês Barroso¹¹, Nicholas J. Wareham¹⁰, Fredrik Karpe⁴, Fredrik Karpe², Katharine R. Owen², Katharine R. Owen⁴, Lon R. Cardon¹, Mark Walker¹², Graham A. Hitman¹³, Graham A. Hitman¹⁴, Colin N. A. Palmer¹⁵, Colin N. A. Palmer¹⁶, Alex S. F. Doney¹⁶, Alex S. F. Doney¹⁵, Andrew D. Morris¹⁵, George Davey Smith¹, Andrew T. Hattersley, Mark I. McCarthy - Show less +52 more•Institutions (16)

University of Bristol¹, Churchill Hospital², Wellcome Trust Centre for Human Genetics³, University of Oxford⁴, National Health Service⁵, University of London⁶, Imperial College London⁷, University of Oulu⁸, National Institutes of Health⁹, Medical Research Council¹⁰, Wellcome Trust Sanger Institute¹¹, Newcastle University¹², Royal London Hospital¹³, Queen Mary University of London¹⁴, Ninewells Hospital¹⁵, University of Dundee¹⁶

11 May 2007-Science

TL;DR: A genome-wide search for type 2 diabetes–susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI).

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Abstract: Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.

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4,184 citations

"Dynamic RNA Modifications in Gene E..." refers background in this paper

...FTO, initially identified by genome-wide association studies for diabetes predisposition, is required for proper splicing in route to adipogenesis (Frayling et al., 2007; Wu et al., 2017; Zhang et al., 2015; Zhao et al., 2014), while ALKBH5 is required for spermatogenesis in mice (Zheng et al....
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...FTO, initially identified by genome-wide association studies for diabetes predisposition, is required for proper splicing in route to adipogenesis (Frayling et al., 2007; Wu et al., 2017; Zhang et al., 2015; Zhao et al., 2014), while ALKBH5 is required for spermatogenesis in mice (Zheng et al.,…...
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Journal Article•DOI•

Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq

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Dan Dominissini¹, Sharon Moshitch-Moshkovitz¹, Schraga Schwartz², Schraga Schwartz³, Mali Salmon-Divon¹, Lior Ungar⁴, Sivan Osenberg⁴, Sivan Osenberg¹, Karen Cesarkas¹, Jasmine Jacob-Hirsch¹, Ninette Amariglio¹, Martin Kupiec⁴, Rotem Sorek³, Gideon Rechavi⁴, Gideon Rechavi¹ - Show less +11 more•Institutions (4)

Sheba Medical Center¹, Broad Institute², Weizmann Institute of Science³, Tel Aviv University⁴

10 May 2012-Nature

TL;DR: The findings suggest that RNA decoration by m6A has a fundamental role in regulation of gene expression, and a subset of stimulus-dependent, dynamically modulated sites is identified.

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Abstract: An extensive repertoire of modifications is known to underlie the versatile coding, structural and catalytic functions of RNA, but it remains largely uncharted territory. Although biochemical studies indicate that N(6)-methyladenosine (m(6)A) is the most prevalent internal modification in messenger RNA, an in-depth study of its distribution and functions has been impeded by a lack of robust analytical methods. Here we present the human and mouse m(6)A modification landscape in a transcriptome-wide manner, using a novel approach, m(6)A-seq, based on antibody-mediated capture and massively parallel sequencing. We identify over 12,000 m(6)A sites characterized by a typical consensus in the transcripts of more than 7,000 human genes. Sites preferentially appear in two distinct landmarks--around stop codons and within long internal exons--and are highly conserved between human and mouse. Although most sites are well preserved across normal and cancerous tissues and in response to various stimuli, a subset of stimulus-dependent, dynamically modulated sites is identified. Silencing the m(6)A methyltransferase significantly affects gene expression and alternative splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis. Our findings therefore suggest that RNA decoration by m(6)A has a fundamental role in regulation of gene expression.

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3,237 citations

"Dynamic RNA Modifications in Gene E..." refers background in this paper

...1188 Cell 169, June 15, 2017 The second advance came with the use of high-throughput sequencing that provided transcriptome-wide maps of modification sites in both mRNA and lncRNA at 200-nucleotide resolution (Dominissini et al., 2012; Meyer et al., 2012), offering the first view of the m(6)A ‘‘epitranscriptome’’ and revealing distributions of m(6)A mainly in the coding and 30 untranslated regions with a significant enrichment just upstream of the stop codon....
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...Them(6)Amodification directly recruits m(6)A-specific proteins of the YTH domain family (Dominissini et al., 2012)....
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...…use of high-throughput sequencing that provided transcriptome-wide maps of modification sites in both mRNA and lncRNA at 200-nucleotide resolution (Dominissini et al., 2012; Meyer et al., 2012), offering the first view of the m6A ‘‘epitranscriptome’’ and revealing distributions of m6A mainly in…...
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...Them6Amodification directly recruits m6A-specific proteins of the YTH domain family (Dominissini et al., 2012)....
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Journal Article•DOI•

Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop Codons

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Kate D. Meyer¹, Yogesh Saletore¹, Paul Zumbo¹, Olivier Elemento¹, Christopher E. Mason¹, Samie R. Jaffrey¹ - Show less +2 more•Institutions (1)

Cornell University¹

22 Jun 2012-Cell

TL;DR: A method is presented for transcriptome-wide m(6)A localization, which combines m( 6)A-specific methylated RNA immunoprecipitation with next-generation sequencing (MeRIP-Seq) and reveals insights into the epigenetic regulation of the mammalian transcriptome.

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2,839 citations

"Dynamic RNA Modifications in Gene E..." refers background in this paper

...…that provided transcriptome-wide maps of modification sites in both mRNA and lncRNA at 200-nucleotide resolution (Dominissini et al., 2012; Meyer et al., 2012), offering the first view of the m6A ‘‘epitranscriptome’’ and revealing distributions of m6A mainly in the coding and 30…...
[...]
...1188 Cell 169, June 15, 2017 The second advance came with the use of high-throughput sequencing that provided transcriptome-wide maps of modification sites in both mRNA and lncRNA at 200-nucleotide resolution (Dominissini et al., 2012; Meyer et al., 2012), offering the first view of the m(6)A ‘‘epitranscriptome’’ and revealing distributions of m(6)A mainly in the coding and 30 untranslated regions with a significant enrichment just upstream of the stop codon....
[...]

Journal Article•DOI•

N6-methyladenosine-dependent regulation of messenger RNA stability

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Xiao Wang¹, Zhike Lu¹, Adrian Gomez¹, Gary C. Hon², Yanan Yue¹, Dali Han¹, Ye Fu¹, Marc Parisien¹, Qing Dai¹, Guifang Jia¹, Bing Ren², Tao Pan¹, Chuan He¹ - Show less +9 more•Institutions (2)

University of Chicago¹, University of California, San Diego²

02 Jan 2014-Nature

TL;DR: It is shown that m6A is selectively recognized by the human YTH domain family 2 (YTHDF2) ‘reader’ protein to regulate mRNA degradation and established the role of YTH DF2 in RNA metabolism, showing that binding of Y THDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies.

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Abstract: N(6)-methyladenosine (m(6)A) is the most prevalent internal (non-cap) modification present in the messenger RNA of all higher eukaryotes. Although essential to cell viability and development, the exact role of m(6)A modification remains to be determined. The recent discovery of two m(6)A demethylases in mammalian cells highlighted the importance of m(6)A in basic biological functions and disease. Here we show that m(6)A is selectively recognized by the human YTH domain family 2 (YTHDF2) 'reader' protein to regulate mRNA degradation. We identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include non-coding RNAs, with a conserved core motif of G(m(6)A)C. We further establish the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies. The carboxy-terminal domain of YTHDF2 selectively binds to m(6)A-containing mRNA, whereas the amino-terminal domain is responsible for the localization of the YTHDF2-mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m(6)A modification is recognized by selectively binding proteins to affect the translation status and lifetime of mRNA.

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2,699 citations

"Dynamic RNA Modifications in Gene E..." refers background in this paper

...A second YTH family protein, YTHDF2, directly recruits the CCR4-NOT deadenylase complex and accelerates degradation of methylated transcripts (Du et al., 2016; Wang et al., 2014a)....
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...In mouse embryonic stem cells (mESCs), depletion of either 1192 Cell 169, June 15, 2017 Mettl3 or Mettl14 reduces m6A methylation and increases transcript stability (Wang et al., 2014b)....
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...This suggests additional pathways for stabilization of these mRNAs, potentially through additional effector proteins (Wang et al., 2014b)....
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...The deposition ofm6A in mammalian mRNA is catalyzed by a heterodimer of METTL3 and METTL14 and regulated by the association of a subunit protein WTAP (Liu et al., 2014; Ping et al., 2014; Wang et al., 2014b)....
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