bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2020–11–15
fourteen papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. Landscape of N6-Methyladenosine Modification Patterns in Human Ameloblastoma.
  2. The mechanism of m6A methyltransferase METTL3-mediated autophagy in reversing gefitinib resistance in NSCLC cells by β-elemene.
  3. Prognostic risk signature based on the expression of three m6A RNA methylation regulatory genes in kidney renal papillary cell carcinoma.
  4. M6A Regulatory Genes Play an Important Role in the Prognosis, Progression and Immune Microenvironment of Pancreatic Adenocarcinoma.
  5. The role of m6A modification in physiology and disease.
  6. m6A Regulates Liver Metabolic Disorders and Hepatogenous Diabetes.
  7. Dynamic analysis of m6A methylation spectroscopy during progression and reversal of hepatic fibrosis.
  8. Novel Insights into Adipogenesis from the Perspective of Transcriptional and RNA N6-Methyladenosine-Mediated Post-Transcriptional Regulation.
  9. Comparison and Analysis of Computational Methods for Identifying N6 - methyladenosine Sites in Saccharomyces Cerevisiae.
  10. Aberrant Regulation of RNA Methylation During Spermatogenesis.
  11. The m6A methyltransferase METTL3 promotes LPS-induced microglia inflammation through TRAF6/NF-κB pathway.
  12. Advances in the profiling of N6-methyladenosine (m6A) modifications.
  13. The epitranscriptome beyond m6A.
  14. Emerging role of N4-acetylcytidine modification of RNA in gene regulation and cellular functions.
  1. Front Oncol. 2020 ;10 556497
    Landscape of N6-Methyladenosine Modification Patterns in Human Ameloblastoma.
    Xing Niu, Jingping Xu, Jinwen Liu, Lijie Chen, Xue Qiao, Ming Zhong.
       Objective: To comprehensively analyze the global N6-methyladenosine (m6A) modification pattern in ameloblastoma.
    Methods: m6A peaks in ameloblastoma and normal oral tissues were detected by MeRIP-seq. Differentially methylated m6A sites within messenger RNAs (mRNAs), long no-coding RNA (lncRNAs) and circular RNA (circRNAs) were identified, followed by functional enrichment analysis. By comprehensively analyzing MeRIP-seq and RNA-seq data, differentially expressed mRNAs, lncRNAs and circRNAs containing differentially methylated sites were identified. RNA binding proteins (RBPs) were then identified for differentially methylated m6A sites.
    Results: In total, 3,673 differentially methylated m6A sites within coding genes were detected, of which 16.2% (704/3,673) were significantly upmethylated sites in ameloblastoma compared to normal oral tissues. Furthermore, 4,975 differentially methylated m6A sites within lncRNAs were identified, of which 29.4% (1,465/4,975) were upmethylated sites in ameloblastoma. We also found 364 differentially methylated m6A sites within circRNAs, of which 22.5% (82/364) were upmethylated sites in ameloblastoma. Differentially methylated m6A was most often harbored in the CDS (54.10%), followed by 5'UTR (21.71%). Functional enrichment analysis revealed that m6A modification could be involved in the development of ameloblastoma by organism developmental processes. A total of 158 RBPs within differentially methylated m6A sites were identified, which were significantly involved in mRNA metabolic process, mRNA processing, RNA processing, RNA splicing and RNA transport.
    Conclusion: Our findings for the first time provide m6A landscape of human ameloblastoma, which expand the understanding of m6A modifications and uncover regulation of lncRNAs and circRNAs through m6A modification in ameloblastoma.
    Keywords:  ameloblastoma; circular RNA; long noncoding RNA; m6A modification; messenger RNA
    DOI:  https://doi.org/10.3389/fonc.2020.556497
  2. Cell Death Dis. 2020 Nov 11. 11(11): 969
    The mechanism of m6A methyltransferase METTL3-mediated autophagy in reversing gefitinib resistance in NSCLC cells by β-elemene.
    Shuiping Liu, Qiujie Li, Guohua Li, Qin Zhang, Lvjia Zhuo, Xuemeng Han, Mingming Zhang, Xiaying Chen, Ting Pan, Lili Yan, Ting Jin, Jianjun Wang, Qun Lv, Xinbing Sui, Tian Xie.
      N6-methyladenosine (m6A) modification can alter gene expression by regulating RNA splicing, stability, translocation, and translation. Emerging evidence shows that m6A modification plays an important role in cancer development and progression, including cell proliferation, migration and invasion, cell apoptosis, autophagy, and drug resistance. Until now, the role of m6A modification mediated autophagy in cancer drug resistance is still unclear. In this study, we found that m6A methyltransferase METTL3-mediated autophagy played an important role in reversing gefitinib resistance by β-elemene in non-small cell lung cancer (NSCLC) cells. Mechanistically, in vitro and in vivo studies indicated that β-elemene could reverse gefitinib resistance in NSCLC cells by inhibiting cell autophagy process in a manner of chloroquine. β-elemene inhibited the autophagy flux by preventing autophagic lysosome acidification, resulting in increasing expression of SQSTM1 and LC3B-II. Moreover, both β-elemene and gefitinib decreased the level of m6A methylation of gefitinib resistance cells. METTL3 was higher expressed in lung adenocarcinoma tissues than that of paired normal tissues, and was involved in the gefitinib resistance of NSCLC cells. Furthermore, METTL3 positively regulated autophagy by increasing the critical genes of autophagy pathway such as ATG5 and ATG7. In conclusion, our study unveiled the mechanism of METTL3-mediated autophagy in reversing gefitinib resistance of NSCLC cells by β-elemene, which shed light on providing potential molecular-therapy target and clinical-treatment method in NSCLC patients with gefitinib resistance.
    DOI:  https://doi.org/10.1038/s41419-020-03148-8
  3. Aging (Albany NY). 2020 Nov 07. 12
    Prognostic risk signature based on the expression of three m6A RNA methylation regulatory genes in kidney renal papillary cell carcinoma.
    Zhuolun Sun, Changying Jing, Chutian Xiao, Tengcheng Li, Yu Wang.
      In this study, we investigated the prognostic significance of the expression of N6-methyladenosine (m6A) RNA methylation regulatory genes in kidney renal papillary cell carcinoma (KIRP). RNA-sequencing data analysis showed that 14 of 20 major m6A RNA methylation regulatory genes were differentially expressed in the KIRP tissues from The Cancer Genome Atlas (TCGA) database. We constructed a prognostic risk signature with three m6A RNA methylation regulatory genes, IGF2BP3, KIAA1429 and HNRNPC, based on the results from univariate and LASSO Cox regression analyses. Multivariate Cox regression analysis confirmed that the risk score based on the three-gene prognostic risk signature was an independent predictive factor in KIRP. The overall survival of high-risk KIRP patients was significantly shorter than the low-risk KIRP patients. Expression of the three prognostic risk-related genes correlated with the AJCC and TNM stages of KIRP patients from TCGA and GEPIA datasets. ROC curve analysis showed that the three-gene prognostic risk signature precisely predicted the 1-year, 3-year and 5-year survival of KIRP patients. These findings demonstrate that expression of three prognostic risk-related m6A RNA methylation regulatory genes accurately predicts survival outcomes in KIRP patients.
    Keywords:  RNA methylation; kidney renal papillary cell carcinoma; m6A; prognostic signature; survival analysis
    DOI:  https://doi.org/10.18632/aging.104053
  4. Cancer Invest. 2020 Nov 12. 1-16
    M6A Regulatory Genes Play an Important Role in the Prognosis, Progression and Immune Microenvironment of Pancreatic Adenocarcinoma.
    Fangshi Xu, Zhengliang Zhang, Miao Yuan, Yidi Zhao, Yang Zhou, Honghong Pei, Ling Bai.
      The specific roles of N6-methyladenosine (m6A) regulatory genes in pancreatic adenocarcinoma (PAAD) have not been fully elucidated. In present study, a novel risk signature was constructed by five m6A-related genes (including METTL3, METTL14, KIAA1429, ALKBH5 and YTHDF1) and was identified as an independent prognostic factor (HR = 13.192) via TCGA (185 samples) databases. The immune abundances of 22 leukocyte subtypes in each PAAD sample were exhibited via the CIBERSORT algorithm. High risk group promoted infiltration levels of Macrophages M0 and M2 cells and decreased that of B cells naive, T cells CD8 and T regulatory cells.
    Keywords:  N6-methyladenosine; Pancreatic adenocarcinoma; immune microenvironment; prognosis; risk signature
    DOI:  https://doi.org/10.1080/07357907.2020.1834576
  5. Cell Death Dis. 2020 Nov 08. 11(11): 960
    The role of m6A modification in physiology and disease.
    Chuan Yang, Yiyang Hu, Bo Zhou, Yulu Bao, Zhibin Li, Chunli Gong, Huan Yang, Sumin Wang, Yufeng Xiao.
      Similar to DNA epigenetic modifications, multiple reversible chemical modifications on RNAs have been uncovered in a new layer of epigenetic modification. N6-methyladenosine (m6A), a modification that occurs in ~30% transcripts, is dynamically regulated by writer complex (methylase) and eraser (RNA demethylase) proteins, and is recognized by reader (m6A-binding) proteins. The effects of m6A modification are reflected in the functional modulation of mRNA splicing, export, localization, translation, and stability by regulating RNA structure and interactions between RNA and RNA-binding proteins. This modulation is involved in a variety of physiological behaviors, including neurodevelopment, immunoregulation, and cellular differentiation. The disruption of m6A modulations impairs gene expression and cellular function and ultimately leads to diseases such as cancer, psychiatric disorders, and metabolic disease. This review focuses on the mechanisms and functions of m6A modification in a variety of physiological behaviors and diseases.
    DOI:  https://doi.org/10.1038/s41419-020-03143-z
  6. Genomics Proteomics Bioinformatics. 2020 Nov 04. pii: S1672-0229(20)30129-7. [Epub ahead of print]
    m6A Regulates Liver Metabolic Disorders and Hepatogenous Diabetes.
    Yuhuan Li, Qingyang Zhang, Guanshen Cui, Fang Zhao, Xin Tian, Bao-Fa Sun, Ying Yang, Wei Li.
      N6-methyladenosine (m6A) is one of the most abundant modifications on mRNAs and plays important roles in various biological processes. The formation of m6A is catalyzed by a methyltransferase complex (MTC) containing a key factor methyltransferase-like 3 (Mettl3). However, the functions of Mettl3 and m6A modification in hepatic lipid and glucose metabolism remain unclear. Here, we showed that both Mettl3 expression and m6A level increased in the livers of mice with high fat diet (HFD)-induced metabolic disorders. Overexpression of Mettl3 aggravated HFD-induced liver metabolic disorders and insulin resistance. In contrast, hepatocyte-specific knockout of Mettl3 significantly alleviated HFD-induced metabolic disorders by slowing weight gain, reducing lipid accumulation, and improving insulin sensitivity. Mechanistically, Mettl3 depletion-mediated m6A loss caused extended RNA half-lives of metabolism-related genes, which consequently protected mice against HFD-induced metabolic syndrome. Our findings reveal a critical role of Mettl3-mediated m6A in HFD-induced metabolic disorders and hepatogenous diabetes.
    Keywords:  High fat diet; Insulin resistance; Lpin1; Mettl3; RNA methylation
    DOI:  https://doi.org/10.1016/j.gpb.2020.06.003
  7. Epigenomics. 2020 Nov 11.
    Dynamic analysis of m6A methylation spectroscopy during progression and reversal of hepatic fibrosis.
    Zhongqi Cui, Nan Huang, Li Liu, Xue Li, Guohui Li, Yan Chen, Qi Wu, Jie Zhang, Shuping Long, Minyi Wang, Fenyong Sun, Yi Shi, Qiuhui Pan.
      Aim: To dynamically analyze the differential m6A methylation during the progression and reversal of hepatic fibrosis. Materials & methods: We induced hepatic fibrosis in C57/BL6 mice by intraperitoneal injection of CCl4. The reversal model of hepatic fibrosis was established by stopping drug after continuous injection of CCl4. Dynamic m6A methylation was evaluated using MeRIP-Seq in the progression and reversal of hepatic fibrosis at different stages. Result: During the hepatic fibrosis, differential m6A methylation was mainly enriched in processes associated with oxidative stress and cytochrome metabolism, while differential m6A methylation was mainly enriched in processes associated with immune response and apoptosis in the hepatic fibrosis reversal. Conclusion: m6A methylation plays an important role in the progression and reversal of hepatic fibrosis.
    Keywords:  N6-methyladenosine; differentially methylated genes; hepatic fibrosis progression; hepatic fibrosis reversal
    DOI:  https://doi.org/10.2217/epi-2019-0365
  8. Adv Sci (Weinh). 2020 Nov;7(21): 2001563
    Novel Insights into Adipogenesis from the Perspective of Transcriptional and RNA N6-Methyladenosine-Mediated Post-Transcriptional Regulation.
    Tongxing Song, Yang Yang, Siwen Jiang, Jian Peng.
      Obesity is a critical risk factor causing the development of metabolic diseases and cancers. Its increasing prevalence worldwide has aroused great concerns of the researchers on adipose development and metabolic function. During adipose expansion, adipogenesis is a way to store lipids as well as to avoid lipotoxicity in other tissues, and may be an approach to offset the negative metabolic effects of obesity. In this Review, the transcriptional regulation of adipogenesis is outlined to characterize numerous biological processes in research on the determination of adipocyte fate and regulation of adipogenic differentiation. Notably, one of the post-transcriptional modifications of mRNA, namely, N6-methyladenosine (m6A), has been recently found to play a role in adipogenesis. Here, the roles of m6A-related enzymes and proteins in adipogenesis, with a particular focus on how these m6A-related proteins function at different stages of adipogenesis, are mainly discussed. The Review also highlights the coordination role of the transcriptional and post-transcriptional (RNA m6A methylation) regulation in adipogenesis and related biological processes. In this context, a better understanding of adipogenesis at both the transcriptional and post-transcriptional levels may facilitate the development of novel strategies to improve metabolic health in obesity.
    Keywords:  RNA m6A modification; adipogenesis; obesity; transcription factors
    DOI:  https://doi.org/10.1002/advs.202001563
  9. Curr Pharm Des. 2020 Nov 08.
    Comparison and Analysis of Computational Methods for Identifying N6 - methyladenosine Sites in Saccharomyces Cerevisiae.
    Pengmian Feng, Lijing Feng, Chaohui Tang.
       BACKGROUND: N 6 -methyladenosine (m6A) plays critical roles in a broad set of biological processes. Knowledge about the precise location of m6A site in the transcriptome is vital for deciphering its biological functions. Although experimental techniques have made substantial contributions to identify m6A, they are still labor intensive and time consuming. As good complements to experimental methods, in the past few years, a series of computational approaches have been proposed to identify m6A sites.
    METHODS: In order to facilitate researchers to select appropriate methods for identifying m6A sites, it is necessary to give a comprehensive review and comparison on existing methods.
    RESULTS: Since researches on m6A in Saccharomyces cerevisiae are relatively clear, in this review, we summarized recent progresses on computational prediction of m6A sites in S. cerevisiae and assessed the performance of existing computational methods. Finally, future directions of computationally identifying m6A sites were presented.
    CONCLUSION: Taken together, we anticipate that this review will provide important guides for computational analysis of m 6A modifications.
    Keywords:  N6 -methyladenosine; RNA modification; Web server; epitranscriptome; feature representation; machine learning
    DOI:  https://doi.org/10.2174/1381612826666201109110703
  10. Reprod Domest Anim. 2020 Nov 11.
    Aberrant Regulation of RNA Methylation During Spermatogenesis.
    Dandan Zhong, Mengjie Chen, Lei Zhang, Hong Chen, Deshun Shi, Qingyou Liu, Hui Li.
      Natural modifications of cellular RNA include various chemical modifications, such as N6-methyladenosine (m6 A), which enable the orderly metabolism and function of RNA structural diversity, thereby affecting gene expression. Spermatogenesis is a complex differentiating developmental process, which includes the proliferation of spermatogonial stem cells, spermatocyte meiosis and sperm maturation. Emerging evidence have shown that RNA methylation can influence RNA splicing, exportation and translation, which are controlled in the male germline in order to ensure coordinated gene expression. In this review, we summarize the typical characteristics of different types of RNA methylation during the process of spermatogenesis. In particular, we emphasize the functions of the RNA methylation effectors during the male germ cell development.
    Keywords:  N6-methyladenosine; RNA methylation; gene expression; spermatogenesis
    DOI:  https://doi.org/10.1111/rda.13856
  11. Neuroreport. 2020 Nov 06.
    The m6A methyltransferase METTL3 promotes LPS-induced microglia inflammation through TRAF6/NF-κB pathway.
    Linbao Wen, Wei Sun, Dayong Xia, Yanming Wang, Junpeng Li, Song Yang.
       OBJECTIVES: Microglia are the main effectors in the inflammatory process of the central nervous system. Once overactivated, microglia may release pro-inflammatory cytokines (IL-1β, IL-6, TNF-α and IL-18, etc.) and accelerate neurodegeneration. Here, we aimed to explore the mechanism of how m6A methyltransferase METTL3 affects the inflammatory response of microglia, appropriately inhibiting the overactivation of microglia.
    MATERIALS AND METHODS: Lipopolysaccharide (LPS) was used to construct a cellular inflammation model in vitro. To evaluate the expression of METTL3 and inflammatory cytokines (IL-1β, IL-6, TNF-α and IL-18) in cells, RT-PCR and ELISA were carried out. The related protein (TRAF6, NF-κB and I-κB) expression was examined adopting Western blot. Dot blot experiment was used to assess the effect of regulating METTL3 on the m6A level. Methylated RNA immunoprecipitation reaction was used to measure the effect of METTL3 on the m6A level of TRAF6 mRNA 3'-UTR. The co-immunoprecipitation experiment (IP) proved that METTL3 combines with TRAF6.
    RESULTS: In LPS-mediated microglial inflammation, METTL3 expression was increased, and the expression of inflammatory cytokines (IL-1β, IL-6, TNF-α and IL-18) and inflammatory proteins (TRAF6 and NF-κB) were upregulated. METTL3 level was positively correlated with TRAF6, and the two proteins could bind to each other. Overexpression of METTL3 promoted the activation of the TRAF6-NF-κB pathway in an m6A-dependent manner, and inhibiting NF-κB attenuated METTL3-mediated microglial activation.
    CONCLUSION: METTL3 promotes LPS-induced microglial inflammation by activating the TRAF6-NF-κB pathway.
    DOI:  https://doi.org/10.1097/WNR.0000000000001550
  12. Biotechnol Adv. 2020 Nov 09. pii: S0734-9750(20)30158-0. [Epub ahead of print] 107656
    Advances in the profiling of N6-methyladenosine (m6A) modifications.
    Hong-Xiang Zheng, Xian-Sheng Zhang, Na Sui.
      Over 160 RNA modifications have been identified, including N7-methylguanine (m7G), N6-methyladenosine (m6A), and 5-methylcytosine (m5C). These modifications play key roles in regulating the fate of RNA. In eukaryotes, m6A is the most abundant mRNA modification, accounting for over 80% of all RNA methylation modifications. Highly dynamic m6A modification may exert important effects on organismal reproduction and development. Significant advances in understanding the mechanism of m6A modification have been made using immunoprecipitation, chemical labeling, and site-directed mutagenesis, combined with next-generation sequencing. Single-molecule real-time and nanopore direct RNA sequencing (DRS) approaches provide additional ways to study RNA modifications at the cellular level. In this review, we explore the technical history of identifying m6A RNA modifications, emphasizing technological advances in detecting m6A modification. In particular, we discuss the challenge of generating accurate dynamic single-base resolution m6A maps and also strategies for improving detection specificity. Finally, we outline a roadmap for future research in this area, focusing on the application of RNA epigenetic modification, represented by m6A modification.
    Keywords:  N(6)-methyladenosine; Nanopore DRS; Next-generation sequencing; SMRT; m(6)A-mapping
    DOI:  https://doi.org/10.1016/j.biotechadv.2020.107656
  13. Nat Rev Genet. 2020 Nov 13.
    The epitranscriptome beyond m6A.
    David Wiener, Schraga Schwartz.
      Following its transcription, RNA can be modified by >170 chemically distinct types of modifications - the epitranscriptome. In recent years, there have been substantial efforts to uncover and characterize the modifications present on mRNA, motivated by the potential of such modifications to regulate mRNA fate and by discoveries and advances in our understanding of N6-methyladenosine (m6A). Here, we review our knowledge regarding the detection, distribution, abundance, biogenesis, functions and possible mechanisms of action of six of these modifications - pseudouridine (Ψ), 5-methylcytidine (m5C), N1-methyladenosine (m1A), N4-acetylcytidine (ac4C), ribose methylations (Nm) and N7-methylguanosine (m7G). We discuss the technical and analytical aspects that have led to inconsistent conclusions and controversies regarding the abundance and distribution of some of these modifications. We further highlight shared commonalities and important ways in which these modifications differ with respect to m6A, based on which we speculate on their origin and their ability to acquire functions over evolutionary timescales.
    DOI:  https://doi.org/10.1038/s41576-020-00295-8
  14. Mol Biol Rep. 2020 Nov 10.
    Emerging role of N4-acetylcytidine modification of RNA in gene regulation and cellular functions.
    R Karthiya, S Mohammed Wasil, Piyush Khandelia.
      Post-transcriptional chemical modification of RNA is rapidly emerging as a key player in regulating gene expression and has propelled the development of 'epitranscriptomics' or 'RNA epigenetics' as a frontier area of research. Several RNA modifications are known to decorate RNAs and impact its structure and function. One such recently discovered modification is acetylation of RNA i.e. N4-acetylcytidine (ac4C) chemical modification. N4-acetylcytidine is an ancient and evolutionarily conserved modification, which maps to a wide spectrum of RNAs from archaea bacteria to humans. This modification results in a variety of functional outcomes which impact normal development and disease. In this review, we summarize the recent progress, emerging methods, biological implications and the future challenges for ac4C modification.
    Keywords:  Gene regulation; N4-acetylcytidine; RNA acetylation; RNA modification; ac4C
    DOI:  https://doi.org/10.1007/s11033-020-05963-w
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