scholarly journals METTL3 counteracts premature aging via m6A-dependent stabilization of MIS12 mRNA

2020 ◽  
Vol 48 (19) ◽  
pp. 11083-11096
Author(s):  
Zeming Wu ◽  
Yue Shi ◽  
Mingming Lu ◽  
Moshi Song ◽  
Zihui Yu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cellular Senescence ◽  
Messenger Rna ◽  
Transcriptional Profiling ◽  
Human Mesenchymal Stem Cell ◽  
Premature Aging ◽  
Biological Processes ◽  
Rna Methylation ◽  
Progeroid Syndromes ◽  
M6a Rna Methylation

Abstract N6-Methyladenosine (m6A) messenger RNA methylation is a well-known epitranscriptional regulatory mechanism affecting central biological processes, but its function in human cellular senescence remains uninvestigated. Here, we found that levels of both m6A RNA methylation and the methyltransferase METTL3 were reduced in prematurely senescent human mesenchymal stem cell (hMSC) models of progeroid syndromes. Transcriptional profiling of m6A modifications further identified MIS12, for which m6A modifications were reduced in both prematurely senescent hMSCs and METTL3-deficient hMSCs. Knockout of METTL3 accelerated hMSC senescence whereas overexpression of METTL3 rescued the senescent phenotypes. Mechanistically, loss of m6A modifications accelerated the turnover and decreased the expression of MIS12 mRNA while knockout of MIS12 accelerated cellular senescence. Furthermore, m6A reader IGF2BP2 was identified as a key player in recognizing and stabilizing m6A-modified MIS12 mRNA. Taken together, we discovered that METTL3 alleviates hMSC senescence through m6A modification-dependent stabilization of the MIS12 transcript, representing a novel epitranscriptional mechanism in premature stem cell senescence.

scholarly journals The Role of m6A Ribonucleic Acid Modification in the Occurrence of Atherosclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jie Fu ◽  
Xinghui Cui ◽  
Xiaoyun Zhang ◽  
Min Cheng ◽  
Xiaoxia Li ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Biological Activities ◽  
Rna Modification ◽  
Acid Modification ◽  
Rna Methylation ◽  
Mrna Metabolism ◽  
Modification Process ◽  
M6a Rna Methylation ◽  
The Relationship

The N6-methyladenosine (m6A) modification is the most abundant epitranscriptomic modification in eukaryotic messenger RNA (mRNA). The m6A modification process is jointly regulated by various enzymes and proteins, such as methyltransferases, demethylases and related m6A-binding proteins. The process is dynamic and reversible, and it plays an essential role in mRNA metabolism and various biological activities. Recently, an increasing number of researchers have confirmed that the onset and development of many diseases are closely associated with the molecular biological mechanism of m6A RNA methylation. This study focuses on the relationship between m6A RNA modification and atherosclerosis (AS). It thoroughly summarizes the mechanisms and processes of m6A RNA modification in AS-related cells and the relationships between m6A RNA modification and AS risk factors, and it provides a reference for exploring new targets for the early diagnosis and treatment of AS.

scholarly journals GENE-25. LOSS OF m6A RNA METHYLATION DURING GLIOMA STEM CELL DIFFERENTIATION IS REGULATED BY MIRNAS AND PROMOTES TRANSLATION EFFICIENCY

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi108-vi108
Author(s):  
John Zepecki ◽  
Eduardo Fajardo ◽  
Kristin Snyder ◽  
Charlotte Guetta-Terrier ◽  
Oliver Tang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Stem Cell Differentiation ◽  
Translation Efficiency ◽  
Glioma Stem Cell ◽  
Rna Methylation ◽  
M6a Rna Methylation

Analysis of the expression patterns and clinical relevance of m6A regulators in 33 cancer types

2021 ◽  
Author(s):  
Chundi Gao ◽  
Haiyang Yu ◽  
Huayao Li ◽  
Cun Liu ◽  
Xiaoran Ma ◽  
...  
Keyword(s):  
Drug Sensitivity ◽  
Clinical Phenotype ◽  
Expression Patterns ◽  
Biological Processes ◽  
Rna Methylation ◽  
Regulatory Factors ◽  
Cancer Types ◽  
M6a Rna Methylation ◽  
Clinical Drug

Background: The role of N6-methyladenine (m6A) RNA methylation in a variety of biological processes is gradually being revealed. Methods: Here, we systematically describe the correlation between the expression pattern of m6A RNA methylation regulatory factors and clinical phenotype, immunity, drug sensitivity, stem cells and prognosis in more than 10,000 samples of 33 types of cancer. Results: The results show that there are significant differences in the expression of 20 m6A RNA methylation regulatory factors in different cancers, and there was a significant correlation with the analysis indicators. Conclusion: In this study, the m6A RNA methylation regulatory factor was found not only to potentially assist in stratifying the prognosis but also to predict or improve the sensitivity of clinical drug therapy.

scholarly journals WITMSG: Large-scale Prediction of Human Intronic m6A RNA Methylation Sites from Sequence and Genomic Features

2020 ◽  
Vol 21 (1) ◽  
pp. 67-76 ◽  
Author(s):  
Lian Liu ◽  
Xiujuan Lei ◽  
Jia Meng ◽  
Zhen Wei
Keyword(s):  
Large Scale ◽  
Cross Validation ◽  
Rna Localization ◽  
Training Data ◽  
Biological Processes ◽  
Computational Framework ◽  
Rna Methylation ◽  
M6a Rna Methylation ◽  
First Time ◽  
Fold Cross Validation

Introduction: N6-methyladenosine (m6A) is one of the most widely studied epigenetic modifications. It plays important roles in various biological processes, such as splicing, RNA localization and degradation, many of which are related to the functions of introns. Although a number of computational approaches have been proposed to predict the m6A sites in different species, none of them were optimized for intronic m6A sites. As existing experimental data overwhelmingly relied on polyA selection in sample preparation and the intronic RNAs are usually underrepresented in the captured RNA library, the accuracy of general m6A sites prediction approaches is limited for intronic m6A sites prediction task. Methodology: A computational framework, WITMSG, dedicated to the large-scale prediction of intronic m6A RNA methylation sites in humans has been proposed here for the first time. Based on the random forest algorithm and using only known intronic m6A sites as the training data, WITMSG takes advantage of both conventional sequence features and a variety of genomic characteristics for improved prediction performance of intron-specific m6A sites. Results and Conclusion: It has been observed that WITMSG outperformed competing approaches (trained with all the m6A sites or intronic m6A sites only) in 10-fold cross-validation (AUC: 0.940) and when tested on independent datasets (AUC: 0.946). WITMSG was also applied intronome-wide in humans to predict all possible intronic m6A sites, and the prediction results are freely accessible at http://rnamd.com/intron/.

YTHDF2 promotes the liver cancer stem cell phenotype and cancer metastasis by regulating OCT4 expression via m6A RNA methylation

Oncogene ◽  
2020 ◽  
Vol 39 (23) ◽  
pp. 4507-4518 ◽  
Author(s):  
Chuanzhao Zhang ◽  
Shanzhou Huang ◽  
Hongkai Zhuang ◽  
Shiye Ruan ◽  
Zixuan Zhou ◽  
...  
Keyword(s):  
Stem Cell ◽  
Liver Cancer ◽  
Cancer Metastasis ◽  
Cell Phenotype ◽  
Rna Methylation ◽  
Oct4 Expression ◽  
Cancer Stem Cell Phenotype ◽  
M6a Rna Methylation ◽  
Liver Cancer Stem Cell ◽  
Stem Cell Phenotype

scholarly journals The Distinct Function of p21Waf1/Cip1 With p16Ink4a in Modulating Aging Phenotypes of Werner Syndrome by Affecting Tissue Homeostasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yongjin Zhang ◽  
Chihao Shao ◽  
Haili Li ◽  
Kun Wu ◽  
Lixin Gong ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Stem Cell ◽  
Cellular Senescence ◽  
Cellular Proliferation ◽  
Werner Syndrome ◽  
Survival Curve ◽  
Cell Cycle Control ◽  
Tissue Homeostasis ◽  
Premature Aging

Human Werner syndrome (WS) is an autosomal recessive progeria disease. A mouse model of WS manifests the disease through telomere dysfunction-induced aging phenotypes, which might result from cell cycle control and cellular senescence. Both p21Waf1/Cip1 (p21, encoded by the Cdkn1a gene) and p16Ink4a (p16, encoded by the Ink4a gene) are cell cycle inhibitors and are involved in regulating two key pathways of cellular senescence. To test the effect of p21 and p16 deficiencies in WS, we crossed WS mice (DKO) with p21–/– or p16–/– mice to construct triple knockout (p21-TKO or p16-TKO) mice. By studying the survival curve, bone density, regenerative tissue (testis), and stem cell capacity (intestine), we surprisingly found that p21-TKO mice displayed accelerated premature aging compared with DKO mice, while p16-TKO mice showed attenuation of the aging phenotypes. The incidence of apoptosis and cellular senescence were upregulated in p21-TKO mice tissue and downregulated in p16-TKO mice. Surprisingly, cellular proliferation in p21-TKO mice tissue was also upregulated, and the p21-TKO mice did not show telomere shortening compared with age-matched DKO mice, although p16-TKO mice displayed obvious enhancement of telomere lengthening. Consistent with these phenotypes, the SIRT1-PGC1 pathway was upregulated in p16-TKO but downregulated in p21-TKO compared with DKO mouse embryo fibroblasts (MEFs). However, the DNA damage response pathway was highly activated in p21-TKO, but rescued in p16-TKO, compared with DKO MEFs. These data suggest that p21 protected the stem cell reservoir by regulating cellular proliferation and turnover at a proper rate and that p21 loss in WS activated fairly severe DNA damage responses (DDR), which might cause an abnormal increase in tissue homeostasis. On the other hand, p16 promoted cellular senescence by inhibiting cellular proliferation, and p16 deficiency released this barrier signal without causing severe DDR.

scholarly journals Current Advances in N6-Methyladenosine Methylation Modification During Bladder Cancer

2022 ◽  
Vol 12 ◽  
Author(s):  
Qiang Liu
Keyword(s):  
Bladder Cancer ◽  
Messenger Rna ◽  
Incidence Rates ◽  
Tumor Formation ◽  
Rna Methylation ◽  
Pathological Type ◽  
Bladder Urothelial Carcinoma ◽  
High Incidence ◽  
M6a Rna Methylation ◽  
Well Differentiated

N6-methyladenosine (m6A) is a dynamic, reversible post-transcriptional modification, and the most common internal modification of eukaryotic messenger RNA (mRNA). Considerable evidence now shows that m6A alters gene expression, thereby regulating cell self-renewal, differentiation, invasion, and apoptotic processes. M6A methylation disorders are directly related to abnormal RNA metabolism, which may lead to tumor formation. M6A methyltransferase is the dominant catalyst during m6A modification; it removes m6A demethylase, promotes recognition by m6A binding proteins, and regulates mRNA metabolic processes. Bladder cancer (BC) is a urinary system malignant tumor, with complex etiology and high incidence rates. A well-differentiated or moderately differentiated pathological type at initial diagnosis accounts for most patients with BC. For differentiated superficial bladder urothelial carcinoma, the prognosis is normally good after surgery. However, due to poor epithelial cell differentiation, BC urothelial cell proliferation and infiltration may lead to invasive or metastatic BC, which lowers the 5-years survival rate and significantly affects clinical treatments in elderly patients. Here, we review the latest progress in m6A RNA methylation research and investigate its regulation on BC occurrence and development.

scholarly journals m6A RNA Methylation Maintains Hematopoietic Stem Cell Identity and Symmetric Commitment

Cell Reports ◽  
2019 ◽  
Vol 28 (7) ◽  
pp. 1703-1716.e6 ◽  
Author(s):  
Yuanming Cheng ◽  
Hanzhi Luo ◽  
Franco Izzo ◽  
Brian F. Pickering ◽  
Diu Nguyen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Cell Identity ◽  
Hematopoietic Stem ◽  
Rna Methylation ◽  
M6a Rna Methylation
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