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N-6-methyladenosine RNA

Ann Fiegen Durbin, Chen Wang, Joseph Marcotrigiano, Lee Gehrke
UNLABELLED: Invading pathogen nucleic acids are recognized and bound by cytoplasmic (retinoic acid-inducible gene I [RIG-I]-like) and membrane-bound (Toll-like) pattern recognition receptors to activate innate immune signaling. Modified nucleotides, when present in RNA molecules, diminish the magnitude of these signaling responses. However, mechanisms explaining the blunted signaling have not been elucidated. In this study, we used several independent biological assays, including inhibition of virus replication, RIG-I:RNA binding assays, and limited trypsin digestion of RIG-I:RNA complexes, to begin to understand how RNAs containing modified nucleotides avoid or suppress innate immune signaling...
2016: MBio
Chyi-Ying A Chen, Ann-Bin Shyu
mRNA is the molecule that conveys genetic information from DNA to the translation apparatus. mRNAs in all organisms display a wide range of stability, and mechanisms have evolved to selectively and differentially regulate individual mRNA stability in response to intracellular and extracellular cues. In recent years, three seemingly distinct aspects of RNA biology-mRNA N(6)-methyladenosine (m6A) modification, alternative 3' end processing and polyadenylation (APA), and mRNA codon usage-have been linked to mRNA turnover, and all three aspects function to regulate global mRNA stability in cis...
September 16, 2016: Trends in Biochemical Sciences
Deepak P Patil, Chun-Kan Chen, Brian F Pickering, Amy Chow, Constanza Jackson, Mitchell Guttman, Samie R Jaffrey
The long non-coding RNA X-inactive specific transcript (XIST) mediates the transcriptional silencing of genes on the X chromosome. Here we show that, in human cells, XIST is highly methylated with at least 78 N(6)-methyladenosine (m(6)A) residues-a reversible base modification of unknown function in long non-coding RNAs. We show that m(6)A formation in XIST, as well as in cellular mRNAs, is mediated by RNA-binding motif protein 15 (RBM15) and its paralogue RBM15B, which bind the m(6)A-methylation complex and recruit it to specific sites in RNA...
September 7, 2016: Nature
Gianluigi Lichinchi, Shang Gao, Yogesh Saletore, Gwendolyn Michelle Gonzalez, Vikas Bansal, Yinsheng Wang, Christopher E Mason, Tariq M Rana
N(6)-methyladenosine (m(6)A) is the most prevalent internal modification of eukaryotic mRNA. Very little is known of the function of m(6)A in the immune system or its role in host-pathogen interactions. Here, we investigate the topology, dynamics and bidirectional influences of the viral-host RNA methylomes during HIV-1 infection of human CD4 T cells. We show that viral infection triggers a massive increase in m(6)A in both host and viral mRNAs. In HIV-1 mRNA, we identified 14 methylation peaks in coding and noncoding regions, splicing junctions and splicing regulatory sequences...
2016: Nature Microbiology
Xiaodong Cui, Jia Meng, Shaowu Zhang, Manjeet K Rao, Yidong Chen, Yufei Huang
BACKGROUND: The recent advent of the state-of-art high throughput sequencing technology, known as Methylated RNA Immunoprecipitation combined with RNA sequencing (MeRIP-seq) revolutionizes the area of mRNA epigenetics and enables the biologists and biomedical researchers to have a global view of N (6)-Methyladenosine (m(6)A) on transcriptome. Yet there is a significant need for new computation tools for processing and analysing MeRIP-Seq data to gain a further insight into the function and m(6)A mRNA methylation...
2016: BMC Genomics
Lisha Shen, Zhe Liang, Xiaofeng Gu, Ying Chen, Zhi Wei Norman Teo, Xingliang Hou, Weiling Maggie Cai, Peter C Dedon, Lu Liu, Hao Yu
N(6)-Methyladenosine (m(6)A) represents the most prevalent internal modification on mRNA and requires a multicomponent m(6)A methyltransferase complex in mammals. How their plant counterparts determine the global m(6)A modification landscape and its molecular link to plant development remain unknown. Here we show that FKBP12 INTERACTING PROTEIN 37 KD (FIP37) is a core component of the m(6)A methyltransferase complex, which underlies control of shoot stem cell fate in Arabidopsis. The mutants lacking FIP37 exhibit massive overproliferation of shoot meristems and a transcriptome-wide loss of m(6)A RNA modifications...
July 25, 2016: Developmental Cell
Benoit Molinie, Jinkai Wang, Kok Seong Lim, Roman Hillebrand, Zhi-Xiang Lu, Nicholas Van Wittenberghe, Benjamin D Howard, Kaveh Daneshvar, Alan C Mullen, Peter Dedon, Yi Xing, Cosmas C Giallourakis
N(6)-Methyladenosine (m(6)A) is a widespread, reversible chemical modification of RNA molecules, implicated in many aspects of RNA metabolism. Little quantitative information exists as to either how many transcript copies of particular genes are m(6)A modified ('m(6)A levels') or the relationship of m(6)A modification(s) to alternative RNA isoforms. To deconvolute the m(6)A epitranscriptome, we developed m(6)A-level and isoform-characterization sequencing (m(6)A-LAIC-seq). We found that cells exhibit a broad range of nonstoichiometric m(6)A levels with cell-type specificity...
August 2016: Nature Methods
Nagaraja Tirumuru, Boxuan Simen Zhao, Wuxun Lu, Zhike Lu, Chuan He, Li Wu
The internal N(6)-methyladenosine (m(6)A) methylation of eukaryotic nuclear RNA controls post-transcriptional gene expression, which is regulated by methyltransferases (writers), demethylases (erasers), and m(6)A-binding proteins (readers) in cells. The YTH domain family proteins (YTHDF1-3) bind to m(6)A-modified cellular RNAs and affect RNA metabolism and processing. Here, we show that YTHDF1-3 proteins recognize m(6)A-modified HIV-1 RNA and inhibit HIV-1 infection in cell lines and primary CD4(+) T-cells...
2016: ELife
Thomas Philipp Hoernes, Alexander Hüttenhofer, Matthias David Erlacher
The expression of a gene is a tightly regulated process and is exerted by a myriad of different mechanisms. Recently, RNA modifications located in coding sequences of mRNAs, have been identified as potential regulators of gene expression. N(6)-methyladenosine (m(6)A), 5-methylcytosine (m(5)C), pseudouridine (Ψ) and N(1)-methyladenosine (m(1)A) have been found within open reading frames of mRNAs. The presence of these mRNA modifications has been implicated to modulate the fate of an mRNA, ranging from maturation to its translation and even degradation...
September 2016: RNA Biology
Thomas Philipp Hoernes, Matthias David Erlacher
RNA modifications are indispensable for the translation machinery to provide accurate and efficient protein synthesis. Whereas the importance of transfer RNA (tRNA) and ribosomal RNA (rRNA) modifications has been well described and is unquestioned for decades, the significance of internal messenger RNA (mRNA) modifications has only recently been revealed. Novel experimental methods have enabled the identification of thousands of modified sites within the untranslated and translated regions of mRNAs. Thus far, N (6) -methyladenosine (m(6) A), pseudouridine (Ψ), 5-methylcytosine (m(5) C) and N (1) -methyladenosine (m(1) A) were identified in eukaryal, and to some extent in prokaryal mRNAs...
June 27, 2016: Wiley Interdisciplinary Reviews. RNA
Jocelyn Widagdo, Qiong-Yi Zhao, Marie-Jeanne Kempen, Men Chee Tan, Vikram S Ratnu, Wei Wei, Laura Leighton, Paola A Spadaro, Janette Edson, Victor Anggono, Timothy W Bredy
UNLABELLED: The RNA modification N(6)-methyladenosine (m(6)A) influences mRNA stability and cell-type-specific developmental programming, and is highly abundant in the adult brain. However, it has not been determined whether m(6)A is dynamically regulated by experience. Based on transcriptome-wide profiling of m(6)A, we report that the level of m(6)A increases in the medial prefrontal cortex (mPFC) of mice in response to behavioral experience. The modulation was enriched near the stop codon of mRNAs, including genes related to neuronal plasticity...
June 22, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Wendy V Gilbert, Tristan A Bell, Cassandra Schaening
RNA contains more than 100 distinct modifications that promote the functions of stable noncoding RNAs in translation and splicing. Recent technical advances have revealed widespread and sparse modification of messenger RNAs with N(6)-methyladenosine (m(6)A), 5-methylcytosine (m(5)C), and pseudouridine (Ψ). Here we discuss the rapidly evolving understanding of the location, regulation, and function of these dynamic mRNA marks, collectively termed the epitranscriptome. We highlight differences among modifications and between species that could instruct ongoing efforts to understand how specific mRNA target sites are selected and how their modification is regulated...
June 17, 2016: Science
Ming Zhang, Jia-Wei Sun, Zi Liu, Ming-Wu Ren, Hong-Bin Shen, Dong-Jun Yu
N(6)-methyladenosine (m(6)A) is one of the most common and abundant post-transcriptional RNA modifications found in viruses and most eukaryotes. m(6)A plays an essential role in many vital biological processes to regulate gene expression. Because of its widespread distribution across the genomes, the identification of m(6)A sites from RNA sequences is of significant importance for better understanding the regulatory mechanism of m(6)A. Although progress has been achieved in m(6)A site prediction, challenges remain...
September 1, 2016: Analytical Biochemistry
Xiang Wang, Jing Feng, Yuan Xue, Zeyuan Guan, Delin Zhang, Zhu Liu, Zhou Gong, Qiang Wang, Jinbo Huang, Chun Tang, Tingting Zou, Ping Yin
Chemical modifications of RNA have essential roles in a vast range of cellular processes. N(6)-methyladenosine (m(6)A) is an abundant internal modification in messenger RNA and long non-coding RNA that can be dynamically added and removed by RNA methyltransferases (MTases) and demethylases, respectively. An MTase complex comprising methyltransferase-like 3 (METTL3) and methyltransferase-like 14 (METTL14) efficiently catalyses methyl group transfer. In contrast to the well-studied DNA MTase, the exact roles of these two RNA MTases in the complex remain to be elucidated...
June 23, 2016: Nature
Ruifan Wu, Denghu Jiang, Yizhen Wang, Xinxia Wang
N (6)-methyladenosine (m(6)A) is the most abundant and reversible internal modification ubiquitously occurring in eukaryotic mRNA, albeit the significant biological roles of m(6)A methylation have remained largely unclear. The well-known DNA and histone methylations play crucial roles in epigenetic modification of biologic processes in eukaryotes. Analogously, the dynamic and reversible m(6)A RNA modification, which is installed by methyltransferase (METTL3, METTL14, and WTAP), reversed by demethylases (FTO, ALKBH5) and mediated by m(6)A-binding proteins (YTHDF1-3, YTHDC1), may also have a profound impact on gene expression regulation...
July 2016: Molecular Biotechnology
Alice Burgess, Rakesh David, Iain Robert Searle
The advent of high-throughput sequencing technologies coupled with new detection methods of RNA modifications has enabled investigation of a new layer of gene regulation - the epitranscriptome. With over 100 known RNA modifications, understanding the repertoire of RNA modifications is a huge undertaking. This review summarizes what is known about RNA modifications with an emphasis on discoveries in plants. RNA ribose modifications, base methylations and pseudouridylation are required for normal development in Arabidopsis, as mutations in the enzymes modifying them have diverse effects on plant development and stress responses...
May 12, 2016: Journal of Integrative Plant Biology
Shui Zou, Joel D W Toh, Kendra H Q Wong, Yong-Gui Gao, Wanjin Hong, Esther C Y Woon
N(6)-Methyladenosine (m6A) is currently one of the most intensively studied post-transcriptional modifications in RNA. Due to its critical role in epigenetics and physiological links to several human diseases, it is also of tremendous biological and medical interest. The m6A mark is dynamically reversed by human demethylases FTO and ALKBH5, however the mechanism by which these enzymes selectively recognise their target transcripts remains unclear. Here, we report combined biophysical and biochemical studies on the specificity determinants of m6A demethylases, which led to the identification of an m6A-mediated substrate discrimination mechanism...
2016: Scientific Reports
Shuibin Lin, Junho Choe, Peng Du, Robinson Triboulet, Richard I Gregory
METTL3 is an RNA methyltransferase implicated in mRNA biogenesis, decay, and translation control through N(6)-methyladenosine (m(6)A) modification. Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells. In contrast to current models that invoke m(6)A reader proteins downstream of nuclear METTL3, we find METTL3 associates with ribosomes and promotes translation in the cytoplasm. METTL3 depletion inhibits translation, and both wild-type and catalytically inactive METTL3 promote translation when tethered to a reporter mRNA...
May 5, 2016: Molecular Cell
Zhang Xiao, Jia Guifang
N(6)-methyladenosine (m(6)A) is one of the most prevalent internal modifications in eukaryotic messenger RNA. The dynamic and reversible modification is installed by methyltransferase complex charactered three subunits: METTL3 (Methyltransferase-like protein 3), METTL14 (Methyltransferase-like protein 14) and WTAP (Wilms tumor 1-associating protein), and erased by two independent demethylases, FTO (Fat mass and obesity associated protein) and ALKBH5 (AlkB homolog 5), in an α-ketoglutarate (α-KG)- and Fe(II)-dependent manner...
April 2016: Yi Chuan, Hereditas
Ying Yang, Wei Huang, Jing-Tao Huang, Fan Shen, Jun Xiong, Er-Feng Yuan, Shan-shan Qin, Ming Zhang, Yu-Qi Feng, Bi-Feng Yuan, Song-Mei Liu
Male infertility is a worldwide medical problem. Asthenozoospermia is a common cause of infertility. Epigenetic modifications of DNA and histones have been shown to influence human infertility, but no research has explored whether N(6)-methyladenosine (m(6)A) level in RNA is associated with asthenozoospermia. Here, we collected a total of 52 semen samples, including 20 asthenozoospermia patients and 32 healthy controls. An LC-ESI-MS/MS method was used to detect m(6)A contents in sperm RNA, and real-time PCR was performed to determine the mRNA expression of demethylase (FTO, ALKBH5), methyltransferase (METTL3, METTL14, WTAP) and an m(6)A-selective-binding protein (YTHDF2)...
2016: Scientific Reports
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