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Dandan Yang, Jing Qiao, Guiying Wang, Yuanyuan Lan, Guoping Li, Xudong Guo, Jiajie Xi, Dan Ye, Songcheng Zhu, Wen Chen, Wenwen Jia, Ye Leng, Xiaoping Wan, Jiuhong Kang
Previous studies have revealed the critical roles of N6-methyladenosine (m6A) modification of mRNA in embryonic stem cells (ESCs), but the biological function of m6A in large intergenic noncoding RNA (lincRNA) is unknown. Here, we showed that the internal m6A modification of linc1281 mediates a competing endogenous RNA (ceRNA) model to regulate mouse ESC (mESC) differentiation. We demonstrated that loss of linc1281 compromises mESC differentiation and that m6A is highly enriched within linc1281 transcripts...
February 26, 2018: Nucleic Acids Research
Yuzhang Du, Guofang Hou, Hailong Zhang, Jinzhuo Dou, Jianfeng He, Yanming Guo, Lian Li, Ran Chen, Yanli Wang, Rong Deng, Jian Huang, Bin Jiang, Ming Xu, Jinke Cheng, Guo-Qiang Chen, Xian Zhao, Jianxiu Yu
The methyltransferase like 3 (METTL3) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for N6-methyladenosine (m6A) modification in diverse RNAs including mRNA, tRNA, rRNA, small nuclear RNA, microRNA precursor and long non-coding RNA. However, the characteristics of METTL3 in activation and post-translational modification (PTM) is seldom understood. Here we find that METTL3 is modified by SUMO1 mainly at lysine residues K177, K211, K212 and K215, which can be reduced by an SUMO1-specific protease SENP1...
February 28, 2018: Nucleic Acids Research
Zhihui Feng, Qimeng Li, Runsha Meng, Baicheng Yi, Qiong Xu
Dental pulp inflammation is a widespread public health problem caused by oral bacterial infections and can progress to pulp necrosis and periapical diseases. N6-methyladenosine (m6A) is a prevalent epitranscriptomic modification in mRNA. Previous studies have demonstrated that m6A methylation plays important roles in cell differentiation, embryonic development and stress responses. However, whether m6A modification affects dental pulp inflammation remains unknown. To address this issue, we investigated the expression of m6A and N6-adenosine methyltransferase (METTL3, METTL14) as well as demethylases (FTO, ALKBH5) and found that the levels of m6A and METTL3 were up-regulated in human dental pulp cells (HDPCs) stimulated by lipopolysaccharide (LPS)...
March 4, 2018: Journal of Cellular and Molecular Medicine
Tingting Hong, Yushu Yuan, Zonggui Chen, Kun Xi, Tianlu Wang, Yalun Xie, Zhiyong He, Haomiao Su, Yu Zhou, Zhi-Jie Tan, Xiaocheng Weng, Xiang Zhou
Innovative detection techniques to achieve precise m6A distribution within mammalian transcriptome can advance our understanding of its biological functions. We specifically introduced the atom-specific replacement of Oxygen with progressively larger atoms (Sulphur and Selenium) at 4-position of deoxythymidine triphosphate to weaken its ability to base pair with m6A, while maintaining A-T* base pair virtually the same as the natural one. 4SedTTP turned out to be an outstanding candidate that endowed m6A with a specific signature of RT truncation, thereby making this "RT-silent" modification detectable with the assistance of m6A demethylase FTO through next-generation sequencing...
February 28, 2018: Journal of the American Chemical Society
Yujiro Nishizawa, Masamitsu Konno, Ayumu Asai, Jun Koseki, Koichi Kawamoto, Norikatsu Miyoshi, Hidekazu Takahashi, Naohiro Nishida, Naotsugu Haraguchi, Daisuke Sakai, Toshihiro Kudo, Taishi Hata, Chu Matsuda, Tsunekazu Mizushima, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii
Recent studies that have emerged on the diversity of RNA modification in tumors suggest their eligibility as bona fide targets in diagnosis and drug discovery. N6-methyladenosine (m6 A) was first reported and is most common in epitranscriptome modification of various RNAs. The YT521-B homology (YTH) domain family are representative m6A-binding proteins, but how the YTH domain family is involved in cancer remains to be clearly understood. Given that clinical sequence data in colorectal cancer indicate that overexpression of YTHDF1 is outstanding among other family members, we studied the role of Ythdf1 and the transcriptional control of YTHDF1...
January 26, 2018: Oncotarget
Mohea Couturier, Ann-Christin Lindås
DNA methylation is the most common epigenetic modification observed in the genomic DNA (gDNA) of prokaryotes and eukaryotes. Methylated nucleobases, N6 -methyl-adenine (m6A), N4 -methyl-cytosine (m4C), and 5-methyl-cytosine (m5C), detected on gDNA represent the discrimination mark between self and non-self DNA when they are part of restriction-modification systems in prokaryotes (Bacteria and Archaea). In addition, m5C in Eukaryotes and m6A in Bacteria play an important role in the regulation of key cellular processes...
2018: Frontiers in Microbiology
Katja Hartstock, Benedikt Nilges, Anna Ovcharenko, Nicolas Cornelissen, Nikolai Puellen, Sebastian Leidel, Andrea Rentmeister
m6A is the most abundant internal modification in eukaryotic mRNA. It is introduced by METTL3-METTL14 and tunes mRNA metabolism, impacting cell differentiation and development. Precise transcriptome-wide assignment of m6A sites is of utmost importance. However, m6A does not interfere with Watson-Crick base pairing making polymerase-based detection challenging. We developed a chemical-biology approach for the precise mapping of methyltransferase (MTase) target sites based on the introduction of a bioorthogonal propargyl group in vitro and in cells...
February 20, 2018: Angewandte Chemie
Kevin Tsai, David G Courtney, Bryan R Cullen
Polyomaviruses are a family of small DNA tumor viruses that includes several pathogenic human members, including Merkel cell polyomavirus, BK virus and JC virus. As is characteristic of DNA tumor viruses, gene expression in polyomaviruses is temporally regulated into an early phase, consisting of the viral regulatory proteins, and a late phase, consisting of the viral structural proteins. Previously, the late transcripts expressed by the prototypic polyomavirus simian virus 40 (SV40) were reported to contain several adenosines bearing methyl groups at the N6 position (m6A), although the precise location of these m6A residues, and their phenotypic effects, have not been investigated...
February 15, 2018: PLoS Pathogens
Xianguang Zhao, Yang Chen, Qiqi Mao, Xiaoyun Jiang, Weiru Jiang, Jiajie Chen, Weijia Xu, Liang Zhong, Xu Sun
In China, hepatocellular carcinoma (HCC) is the most commonly diagnosed cancer and the leading cause of cancer death in men, followed by lung and stomach cancer. There was an urgent need to identify novel prognostic biomarkers for HCC. We explored the expression pattern of m6A related proteins in HCC tissues by using TCGA in this study. We found that the m6A 'reader' YTHDF1 was significantly upregulated in HCC and was positive correlated with pathology stage. Kaplan-Meier analysis showed that Lower YTHDF1 expression level was associated with better survival of HCC patients...
January 28, 2018: Cancer Biomarkers: Section A of Disease Markers
Jun Zhou, Ji Wan, Xin Erica Shu, Yuanhui Mao, Xiao-Min Liu, Xin Yuan, Xingqian Zhang, Martin E Hess, Jens C Brüning, Shu-Bing Qian
The integrated stress response (ISR) facilitates cellular adaptation to stress conditions via the common target eIF2α. During ISR, the selective translation of stress-related mRNAs often relies on alternative mechanisms, such as leaky scanning or reinitiation, but the underlying mechanism remains incompletely understood. Here we report that, in response to amino acid starvation, the reinitiation of ATF4 is not only governed by the eIF2α signaling pathway, but is also subjected to regulation by mRNA methylation in the form of N6-methyladenosine (m6A)...
February 1, 2018: Molecular Cell
Jiangfeng Li, Shuai Meng, Mingjie Xu, Song Wang, Liujia He, Xin Xu, Xiao Wang, Liping Xie
Recent evidence suggests that m6A modifications regulate the progressions of several types of tumors. YTHDF2, an m6A reader, has been implicated in the regulation of hepatocellular carcinoma (HCC). miR-493-3p has been defined as tumor suppressor that inhibits the progressions of several types of cancers. However, the functions and mechanisms of YTHDF2 and the indirect m6A regulated role of miR-493-3p in prostate cancer (PCa) remains to be elusive. In this study, immuno-histochemical (IHC) staining and chromogenic in situ hybridization (CISH) were performed to find YTHDF2 was frequently upregulated but miR-493-3p was downregulated in both PCa tissues and cell lines (DU-145 and PC3) which was negatively correlated with each other...
January 9, 2018: Oncotarget
Weiwei Lai, Jiantao Jia, Bin Yan, Yiqun Jiang, Ying Shi, Ling Chen, Chao Mao, Xiaoli Liu, Haosheng Tang, Menghui Gao, Ya Cao, Shuang Liu, Yongguang Tao
Baicalin hydrate (BH), a natural compound, has been investigated for many years because of its traditional medicinal properties. However, the anti-tumor activities of BH and its epigenetic role in NPC have not been elucidated. In this study, we identified that BH inhibits NPC cell growth in vivo and in vitro by inducing apoptosis and cell cycle arrest. BH epigenetically regulated genome instability by up-regulating the expression of satellite 2 (Sat2), alpha satellite (α-Sat), and major satellite (Major-Sat)...
January 2, 2018: Oncotarget
Hongjing Deng, Jitender Cheema, Hang Zhang, Hugh Woolfenden, Matthew Norris, Zhenshan Liu, Qi Liu, Xiaofei Yang, Minglei Yang, Xian Deng, Xiaofeng Cao, Yiliang Ding
RNA secondary structure plays a critical role in gene regulation. Rice (Oryza sativa L.) is one of the most important food crops in the world. However, RNA structure in rice has scarcely been studied. Here, for the first time we have successfully generated in vivo Structure-seq libraries in rice. We found that the structural flexibility of mRNAs might associate with the dynamics of biological function. Higher N6-methyladenosine (m6A) modification tends to have less RNA structure in 3'UTR. GC content does not significantly affect in vivo mRNA structure to maintain efficient biological processes such as translation...
January 31, 2018: Molecular Plant
Gaëlle H Martin, Christopher Y Park
Three recent studies independently identified the m6 A RNA modifying enzymes METTL3 and METTL14 as critical regulators of differentiation in both normal hematopoiesis and AML pathogenesis. These studies expand the described roles of the epitranscriptome in maintaining the undifferentiated state in somatic stem cells and human cancer.
February 1, 2018: Cell Stem Cell
Zhen Liu, Jianzhi Zhang
C-to-U RNA editing enzymatically converts the base C to U in RNA molecules and could lead to nonsynonymous changes when occurring in coding regions. Hundreds to thousands of coding sites were recently found to be C-to-U edited or editable in humans, but the biological significance of this phenomenon is elusive. Here we test the prevailing hypothesis that nonsynonymous editing is beneficial because it provides a means for tissue- or time-specific regulation of protein function that may be hard to accomplish by mutations due to pleiotropy...
January 27, 2018: Molecular Biology and Evolution
Chenyue Ding, Qinyan Zou, Jie Ding, Mingfa Ling, Wei Wang, Hong Li, Boxian Huang
The N6-methyladenosine (m6A) modification plays a central role in epigenetic regulation of the mammalian transcriptome. m6A can be demethylated by the fat mass- and obesity-associated (FTO) protein and the α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) protein. Much less is known about that whether m6A content is involved in POI (premature ovarian insufficiency) disease. In this case-controlled study, 69 POI and 53 tubal occlusion patients were recruited from the reproduction centers in our hospital...
January 31, 2018: Journal of Cellular Physiology
Baixing Wu, Shichen Su, Deepak P Patil, Hehua Liu, Jianhua Gan, Samie R Jaffrey, Jinbiao Ma
Human hnRNP A2/B1 is an RNA-binding protein that plays important roles in many biological processes, including maturation, transport, and metabolism of mRNA, and gene regulation of long noncoding RNAs. hnRNP A2/B1 was reported to control the microRNAs sorting to exosomes and promote primary microRNA processing as a potential m6A "reader." hnRNP A2/B1 contains two RNA recognition motifs that provide sequence-specific recognition of RNA substrates. Here, we determine crystal structures of tandem RRM domains of hnRNP A2/B1 in complex with various RNA substrates, elucidating specific recognitions of AGG and UAG motifs by RRM1 and RRM2 domains, respectively...
January 29, 2018: Nature Communications
Dongjun Dai, Hanying Wang, Liyuan Zhu, Hongchuan Jin, Xian Wang
N6-methyladenosine (m6A) is the most abundant mRNA modification. With the development of antibody-based sequencing technologies and the findings of m6A-related "writers", "erasers", and "readers", the relationships between m6A and mRNA metabolism are emerging. The m6A modification influences almost every step of RNA metabolism that comprises mRNA processing, mRNA exporting from nucleus to cytoplasm, mRNA translation, mRNA decay, and the biogenesis of long-non-coding RNA (lncRNA) and microRNA (miRNA). Recently, more and more studies have found m6A is associated with cancer, contributing to the self-renewal of cancer stem cell, promotion of cancer cell proliferation, and resistance to radiotherapy or chemotherapy...
January 26, 2018: Cell Death & Disease
Thomas K Ni, Jessica S Elman, Dexter X Jin, Piyush B Gupta, Charlotte Kuperwasser
In cancer, tumor suppressor genes (TSGs) are frequently truncated, causing their encoded products to be non-functional or dominant-negative. We previously showed that premature polyadenylation (pPA) of MAGI3 truncates the gene, switching its functional role from a TSG to a dominant-negative oncogene. Here we report that MAGI3 undergoes pPA at the intron immediately downstream of its large internal exon, which is normally highly modified by N6-methyladenosine (m6A). In breast cancer cells that upregulate MAGI3 pPA , m6A levels in the large internal exon of MAGI3 are significantly reduced compared to cells that do not express MAGI3 pPA ...
January 23, 2018: Scientific Reports
Eva Schöller, Franziska Weichmann, Thomas Treiber, Sam Ringle, Nora Treiber, Andrew Flatley, Regina Feederle, Astrid Bruckmann, Gunter Meister
N6-methyladenine (m6A) is found on many eukaryotic RNAs including mRNAs. M6A modification has been implicated in mRNA stability and turn over, localization or translation efficiency. A heterodimeric enzyme complex composed of METTL3 and METTL14 generates m6A on mRNAs. METTL3/14 is found in the nucleus where it is localized to nuclear speckles and the splicing regulator WTAP is required for this distinct nuclear localization pattern. Although recent crystal structures revealed how the catalytic MT-A70 domains of METTL3 and METTL14 interact with each other, a more global architecture including WTAP and RNA interactions has not been reported so far...
January 18, 2018: RNA
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