scholarly journals RNA methylation in mammalian development and cancer

2021 ◽  
Author(s):  
Peizhe Song ◽  
Subiding Tayier ◽  
Zhihe Cai ◽  
Guifang Jia
Keyword(s):  
Cell Fate ◽  
Cancer Progression ◽  
Rna Modification ◽  
Biological Processes ◽  
Cell Fate Determination ◽  
Mammalian Development ◽  
Rna Modifications ◽  
Temporal And Spatial ◽  
Underlying Mechanisms ◽  
Cellular Components

AbstractSimilar to epigenetic DNA and histone modifications, epitranscriptomic modifications (RNA modifications) have emerged as crucial regulators in temporal and spatial gene expression during eukaryotic development. To date, over 170 diverse types of chemical modifications have been identified upon RNA nucleobases. Some of these post-synthesized modifications can be reversibly installed, removed, and decoded by their specific cellular components and play critical roles in different biological processes. Accordingly, dysregulation of RNA modification effectors is tightly orchestrated with developmental processes. Here, we particularly focus on three well-studied RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), and N1-methyladenosine (m1A), and summarize recent knowledge of underlying mechanisms and critical roles of these RNA modifications in stem cell fate determination, embryonic development, and cancer progression, providing a better understanding of the whole association between epitranscriptomic regulation and mammalian development.

RNA modifications in hematopoietic malignancies: A new research frontier

Blood ◽  
2021 ◽  
Author(s):  
Ying Qing ◽  
Rui Su ◽  
Jianjun Chen
Keyword(s):  
Myeloid Leukemia ◽  
Therapeutic Potential ◽  
Rna Modification ◽  
Biological Functions ◽  
Rna Modifications ◽  
Aberrant Expression ◽  
Protein Coding ◽  
Hematopoietic Malignancies ◽  
Underlying Mechanisms ◽  
New Research

Both protein-coding and noncoding RNAs can be decorated with a wealth of chemical modifications and such modifications coordinately orchestrate gene expression during normal hematopoietic differentiation and development. However, aberrant expression and/or dysfunction of the relevant RNA modification modulators/regulators ("writers", "erasers", and "readers") drive the initiation and progression of hematopoietic malignancies, and targeting these dysregulated modulators holds potent therapeutic potential for the treatment of hematopoietic malignancies. In this review, we summarize current progress in the understanding of the biological functions and underlying mechanisms of RNA modifications in normal and malignant hematopoiesis, with a focus on the N6-methyladenosine (m6A) modification, and discuss the therapeutic potential of targeting RNA modifications for the treatment of hematopoietic malignancies, especially acute myeloid leukemia (AML).

scholarly journals Repurposing RNA sequencing for discovery of RNA modifications in clinical cohorts

2021 ◽  
Vol 7 (32) ◽  
pp. eabd2605
Author(s):  
Kar-Tong Tan ◽  
Ling-Wen Ding ◽  
Chan-Shuo Wu ◽  
Daniel G. Tenen ◽  
Henry Yang
Keyword(s):  
Rna Sequencing ◽  
Cancer Progression ◽  
De Novo ◽  
Rna Modification ◽  
Rna Modifications ◽  
Multiple Cancer ◽  
Patients With Cancer ◽  
Statistical Framework ◽  
Cancer Types ◽  
Nucleotide Resolution

The study of RNA modifications in large clinical cohorts can reveal relationships between the epitranscriptome and human diseases, although this is especially challenging. We developed ModTect (https://github.com/ktan8/ModTect), a statistical framework to identify RNA modifications de novo by standard RNA-sequencing with deletion and mis-incorporation signals. We show that ModTect can identify both known (N1-methyladenosine) and previously unknown types of mRNA modifications (N2,N2-dimethylguanosine) at nucleotide-resolution. Applying ModTect to 11,371 patient samples and 934 cell lines across 33 cancer types, we show that the epitranscriptome was dysregulated in patients across multiple cancer types and was additionally associated with cancer progression and survival outcomes. Some types of RNA modification were also more disrupted than others in patients with cancer. Moreover, RNA modifications contribute to multiple types of RNA-DNA sequence differences, which unexpectedly escape detection by Sanger sequencing. ModTect can thus be used to discover associations between RNA modifications and clinical outcomes in patient cohorts.

scholarly journals N6-methyladenine modification in noncoding RNAs and its function in cancer

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Xinyu Yang ◽  
Xiang Hu ◽  
Jinting Liu ◽  
Ruiqing Wang ◽  
Chen Zhang ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Mammalian Cells ◽  
Rna Modification ◽  
Biological Processes ◽  
Non Coding Rnas ◽  
New Perspective ◽  
Main Component ◽  
Almost All ◽  
Tumor Gene Expression ◽  
Tumor Gene

Abstract Non-coding RNAs are the main component of the extensive transcription results of the mammalian genome. They are not transcribed into proteins but play critical roles in regulating multiple biological processes and affecting cancer progression. m6A modification is one of the most abundant internal RNA modification of mammalian cells, and it involves almost all aspects of RNA metabolism. Recent research revealed tight correlations between m6A modification and ncRNAs and indicated the interaction between m6A and ncRNAs act a pivotal part in the development of cancer. The correlation between m6A modification and ncRNAs provides a new perspective for exploring the potential regulatory mechanism of tumor gene expression, and suggest that m6A modification and ncRNAs may be important prognostic markers and therapeutic targets for multiple cancers. In this review, we summarize the potential regulatory mechanisms between m6A methylation and ncRNAs, highlighting how their relationship affects biological functions in cancer.

scholarly journals RNAWRE: a resource of writers, readers and erasers of RNA modifications

Database ◽  
2020 ◽  
Vol 2020 ◽  
Author(s):  
Fulei Nie ◽  
Pengmian Feng ◽  
Xiaoming Song ◽  
Meng Wu ◽  
Qiang Tang ◽  
...  
Keyword(s):  
Regulatory Mechanisms ◽  
Rna Modification ◽  
Biological Processes ◽  
Biological Functions ◽  
Rna Modifications ◽  
Current Version ◽  
Blast Search

Abstract RNA modifications are involved in various kinds of cellular biological processes. Accumulated evidences have demonstrated that the functions of RNA modifications are determined by the effectors that can catalyze, recognize and remove RNA modifications. They are called ‘writers’, ‘readers’ and ‘erasers’. The identification of RNA modification effectors will be helpful for understanding the regulatory mechanisms and biological functions of RNA modifications. In this work, we developed a database called RNAWRE that specially deposits RNA modification effectors. The current version of RNAWRE stored 2045 manually curated writers, readers and erasers for the six major kinds of RNA modifications, namely Cap, m1A, m6A, m5C, ψ and Poly A. The main modules of RNAWRE not only allow browsing and downloading the RNA modification effectors but also support the BLAST search of the potential RNA modification effectors in other species. We hope that RNAWRE will be helpful for the researches on RNA modifications. Database URL: http://rnawre.bio2db.com

scholarly journals Logic programming to predict cell fate patterns and retrodict genotypes in organogenesis

2014 ◽  
Vol 11 (98) ◽  
pp. 20140245 ◽  
Author(s):  
Benjamin A. Hall ◽  
Ethan Jackson ◽  
Alex Hajnal ◽  
Jasmin Fisher
Keyword(s):  
Cell Fate ◽  
Formal Analysis ◽  
Cell Fate Determination ◽  
Logic Programs ◽  
Vulval Development ◽  
Analysis Techniques ◽  
C Elegans ◽  
Vulval Precursor Cells ◽  
Powerful Approach ◽  
Temporal And Spatial

Caenorhabditis elegans vulval development is a paradigm system for understanding cell differentiation in the process of organogenesis. Through temporal and spatial controls, the fate pattern of six cells is determined by the competition of the LET-23 and the Notch signalling pathways. Modelling cell fate determination in vulval development using state-based models, coupled with formal analysis techniques, has been established as a powerful approach in predicting the outcome of combinations of mutations. However, computing the outcomes of complex and highly concurrent models can become prohibitive. Here, we show how logic programs derived from state machines describing the differentiation of C. elegans vulval precursor cells can increase the speed of prediction by four orders of magnitude relative to previous approaches. Moreover, this increase in speed allows us to infer, or ‘retrodict’, compatible genomes from cell fate patterns. We exploit this technique to predict highly variable cell fate patterns resulting from dig-1 reduced-function mutations and let-23 mosaics. In addition to the new insights offered, we propose our technique as a platform for aiding the design and analysis of experimental data.

scholarly journals RNAmod: an integrated system for the annotation of mRNA modifications

2019 ◽  
Vol 47 (W1) ◽  
pp. W548-W555 ◽  
Author(s):  
Qi Liu ◽  
Richard I Gregory
Keyword(s):  
Cancer Progression ◽  
Messenger Rna ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Integrated System ◽  
Rna Modification ◽  
Specific Gene ◽  
Analysis Tool ◽  
Rna Modifications ◽  
Altered Expression

Abstract Dynamic and reversible RNA modifications such as N6-methyladenosine (m6A) can play important roles in regulating messenger RNA (mRNA) splicing, export, stability and translation. Defective mRNA modification through altered expression of the methyltransferase and/or demethylases results in developmental defects and cancer progression. Identifying modified mRNAs, annotating the distribution of modification sites across the mRNA, as well as characterizing and comparing other modification features are essential for studying the function and elucidating the mechanism of mRNA modifications. Several methods including methylated RNA immunoprecipitation and sequencing (MeRIP-seq) are available for the detection of mRNA modifications. However, a convenient and comprehensive tool to annotate diverse kinds of mRNA modifications in different species is lacking. Here, we developed RNAmod (https://bioinformatics.sc.cn/RNAmod), an interactive, one-stop, web-based platform for the automated analysis, annotation, and visualization of mRNA modifications in 21 species. RNAmod provides intuitive interfaces to show outputs including the distribution of RNA modifications, modification coverage for different gene features, functional annotation of modified mRNAs, and comparisons between different groups or specific gene sets. Furthermore, sites of known RNA modification, as well as binding site data for hundreds of RNA-binding proteins (RBPs) are integrated in RNAmod to help users compare their modification data with known modifications and to explore the relationship with the binding sites of known RBPs. RNAmod is freely available and meets the emerging need for a convenient and comprehensive analysis tool for the fast-developing RNA modification field.

scholarly journals m6A-Atlas: a comprehensive knowledgebase for unraveling the N6-methyladenosine (m6A) epitranscriptome

2020 ◽  
Vol 49 (D1) ◽  
pp. D134-D143
Author(s):  
Yujiao Tang ◽  
Kunqi Chen ◽  
Bowen Song ◽  
Jiongming Ma ◽  
Xiangyu Wu ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
Rna Modification ◽  
Virus Species ◽  
Biological Processes ◽  
Sequence Motifs ◽  
Biological Functions ◽  
Rna Modifications ◽  
User Friendly ◽  
Friendly Graphical User Interface ◽  
Query Visualization

Abstract N 6-Methyladenosine (m6A) is the most prevalent RNA modification on mRNAs and lncRNAs. It plays a pivotal role during various biological processes and disease pathogenesis. We present here a comprehensive knowledgebase, m6A-Atlas, for unraveling the m6A epitranscriptome. Compared to existing databases, m6A-Atlas features a high-confidence collection of 442 162 reliable m6A sites identified from seven base-resolution technologies and the quantitative (rather than binary) epitranscriptome profiles estimated from 1363 high-throughput sequencing samples. It also offers novel features, such as; the conservation of m6A sites among seven vertebrate species (including human, mouse and chimp), the m6A epitranscriptomes of 10 virus species (including HIV, KSHV and DENV), the putative biological functions of individual m6A sites predicted from epitranscriptome data, and the potential pathogenesis of m6A sites inferred from disease-associated genetic mutations that can directly destroy m6A directing sequence motifs. A user-friendly graphical user interface was constructed to support the query, visualization and sharing of the m6A epitranscriptomes annotated with sites specifying their interaction with post-transcriptional machinery (RBP-binding, microRNA interaction and splicing sites) and interactively display the landscape of multiple RNA modifications. These resources provide fresh opportunities for unraveling the m6A epitranscriptomes. m6A-Atlas is freely accessible at: www.xjtlu.edu.cn/biologicalsciences/atlas.

scholarly journals ADAR1 is a new target of METTL3 and plays a pro-oncogenic role in glioblastoma by an editing-independent mechanism

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Valentina Tassinari ◽  
Valeriana Cesarini ◽  
Sara Tomaselli ◽  
Zaira Ianniello ◽  
Domenico Alessandro Silvestris ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Tumor Development ◽  
Rna Modification ◽  
Rna Modifications ◽  
Independent Mechanism ◽  
Tumorigenic Mechanism ◽  
Mrna Fate

Abstract Background N6-methyladenosine (m6A) and adenosine-to-inosine (A-to-I) RNA editing are two of the most abundant RNA modification events affecting adenosines in mammals. Both these RNA modifications determine mRNA fate and play a pivotal role in tumor development and progression. Results Here, we show that METTL3, upregulated in glioblastoma, methylates ADAR1 mRNA and increases its protein level leading to a pro-tumorigenic mechanism connecting METTL3, YTHDF1, and ADAR1. We show that ADAR1 plays a cancer-promoting role independently of its deaminase activity by binding CDK2 mRNA, underlining the importance of ADARs as essential RNA-binding proteins for cell homeostasis as well as cancer progression. Additionally, we show that ADAR1 knockdown is sufficient to strongly inhibit glioblastoma growth in vivo. Conclusions Hence, our findings underscore METTL3/ADAR1 axis as a novel crucial pathway in cancer progression that connects m6A and A-to-I editing post-transcriptional events.

scholarly journals Programmable System of Cas13-Mediated RNA Modification and Its Biological and Biomedical Applications

2021 ◽  
Vol 9 ◽  
Author(s):  
Tian Tang ◽  
Yingli Han ◽  
Yuran Wang ◽  
He Huang ◽  
Pengxu Qian
Keyword(s):  
Cell Fate ◽  
Rna Editing ◽  
Cell Biology ◽  
Rna Stability ◽  
Rna Modification ◽  
Translation Efficiency ◽  
Rna Modifications ◽  
History Of ◽  
Rna Interaction ◽  
Adenosine Deamination

Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas13 has drawn broad interest to control gene expression and cell fate at the RNA level in general. Apart from RNA interference mediated by its endonuclease activity, the nuclease-deactivated form of Cas13 further provides a versatile RNA-guided RNA-targeting platform for manipulating kinds of RNA modifications post-transcriptionally. Chemical modifications modulate various aspects of RNA fate, including translation efficiency, alternative splicing, RNA–protein affinity, RNA–RNA interaction, RNA stability and RNA translocation, which ultimately orchestrate cellular biologic activities. This review summarizes the history of the CRISPR-Cas13 system, fundamental components of RNA modifications and the related physiological and pathological functions. We focus on the development of epi-transcriptional editing toolkits based on catalytically inactive Cas13, including RNA Editing for Programmable A to I Replacement (REPAIR) and xABE (adenosine base editor) for adenosine deamination, RNA Editing for Specific C-to-U Exchange (RESCUE) and xCBE (cytidine base editor) for cytidine deamination and dm6ACRISPR, as well as the targeted RNA methylation (TRM) and photoactivatable RNA m6A editing system using CRISPR-dCas13 (PAMEC) for m6A editing. We further highlight the emerging applications of these useful toolkits in cell biology, disease and imaging. Finally, we discuss the potential limitations, such as off-target editing, low editing efficiency and limitation for AAV delivery, and provide possible optimization strategies.

scholarly journals Modeling of histone modifications reveals formation mechanism and function of bivalent chromatin

2021 ◽  
Author(s):  
Wei Zhao ◽  
Lingxia Qiao ◽  
Shiyu Yan ◽  
Qing Nie ◽  
Lei Zhang
Keyword(s):  
Cell Fate ◽  
Histone Modifications ◽  
Necessary Conditions ◽  
Chromatin State ◽  
Chromatin Domain ◽  
Biological Processes ◽  
Cell Fate Determination ◽  
Repressive Chromatin ◽  
And Function ◽  
Bivalent Chromatin Domain

AbstractBivalent chromatin is characterized by occupation of both activating histone modifications and repressive histone modifications. While bivalent chromatin is known to link with many biological processes, the mechanisms responsible for its multiple functions remain unclear. Here, we develop a mathematical model that involves antagonistic histone modifications H3K4me3 and H3K27me3 to capture the key features of bivalent chromatin. Three necessary conditions for the emergence of bivalent chromatin are identified, including advantageous methylating activity over demethylating activity, frequent noise conversions of modifications, and sufficient nonlinearity. The first condition is further confirmed by analyzing the experimental data from a recent study. Investigation of the composition of bivalent chromatin reveals that bivalent nucleosomes carrying both H3K4me3 and H3K27me3 account for no more than half of nucleosomes at the bivalent chromatin domain. We identify that bivalent chromatin not only allows transitions to multiple states but also serves as a stepping stone to facilitate a step-wise transition between repressive chromatin state and activating chromatin state, and thus elucidate crucial roles of bivalent chromatin in mediating phenotypical plasticity during cell fate determination.

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