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 RNA Modifications in Cancer: Functions, Mechanisms, and Therapeutic Implications

2020 ◽  
Vol 4 (1) ◽  
pp. 221-240 ◽  
Author(s):  
Huilin Huang ◽  
Hengyou Weng ◽  
Xiaolan Deng ◽  
Jianjun Chen
Keyword(s):  
Gene Expression ◽  
Current Knowledge ◽  
Global Gene Expression ◽  
Rna Modifications ◽  
Aberrant Expression ◽  
Protein Coding ◽  
Therapeutic Implications ◽  
Underlying Mechanisms ◽  
Aberrant Rna ◽  
Gene Expression Dysregulation

Over 170 chemical modifications have been identified in protein-coding and noncoding RNAs and shown to exhibit broad impacts on gene expression. Dysregulation of RNA modifications caused by aberrant expression of or mutations in RNA modifiers aberrantly reprograms the epitranscriptome and skews global gene expression, which in turn leads to tumorigenesis and drug resistance. Here we review current knowledge of the functions and underlying mechanisms of aberrant RNA modifications in human cancers, particularly several common RNA modifications, including N6-methyladenosine (m6A), A-to-I editing, pseudouridine (ψ), 5-methylcytosine (m5C), 5-hydroxymethylcytosine (hm5C), N1-methyladenosine (m1A), and N4-acetylcytidine (ac4C), providing insights into therapeutic implications of targeting RNA modifications and the associated machineries for cancer therapy.

scholarly journals Long Non-Coding RNAs and Related Molecular Pathways in the Pathogenesis of Epilepsy

2019 ◽  
Vol 20 (19) ◽  
pp. 4898 ◽  
Author(s):  
Villa ◽  
Lavitrano ◽  
Combi
Keyword(s):  
Biological Processes ◽  
Complete Understanding ◽  
Aberrant Expression ◽  
Protein Coding ◽  
Diagnostic Biomarkers ◽  
Functional Roles ◽  
The Central Nervous System ◽  
Non Coding Rnas ◽  
Underlying Mechanisms ◽  
Coding Capacity

Epilepsy represents one of the most common neurological disorders characterized by abnormal electrical activity in the central nervous system (CNS). Recurrent seizures are the cardinal clinical manifestation. Although it has been reported that the underlying pathological processes include inflammation, changes in synaptic strength, apoptosis, and ion channels dysfunction, currently the pathogenesis of epilepsy is not yet completely understood. Long non-coding RNAs (lncRNAs), a class of long transcripts without protein-coding capacity, have emerged as regulatory molecules that are involved in a wide variety of biological processes. A growing number of studies reported that lncRNAs participate in the regulation of pathological processes of epilepsy and they are dysregulated during epileptogenesis. Moreover, an aberrant expression of lncRNAs linked to epilepsy has been observed both in patients and in animal models. In this review, we summarize latest advances concerning the mechanisms of action and the involvement of the most dysregulated lncRNAs in epilepsy. However, the functional roles of lncRNAs in the disease pathogenesis are still to be explored and we are only at the beginning. Additional studies are needed for the complete understanding of the underlying mechanisms and they would result in the use of lncRNAs as diagnostic biomarkers and novel therapeutic targets.

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.

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 From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 550
Author(s):  
Hironori Adachi ◽  
Martin Hengesbach ◽  
Yi-Tao Yu ◽  
Pedro Morais
Keyword(s):  
Rna Processing ◽  
Therapeutic Potential ◽  
Genetic Disorders ◽  
Mrna Translation ◽  
High Specificity ◽  
Rnase H ◽  
Rna Modification ◽  
Genetic Mutations ◽  
Rna Modifications ◽  
Splicing Defects

Therapeutic oligonucleotides interact with a target RNA via Watson-Crick complementarity, affecting RNA-processing reactions such as mRNA degradation, pre-mRNA splicing, or mRNA translation. Since they were proposed decades ago, several have been approved for clinical use to correct genetic mutations. Three types of mechanisms of action (MoA) have emerged: RNase H-dependent degradation of mRNA directed by short chimeric antisense oligonucleotides (gapmers), correction of splicing defects via splice-modulation oligonucleotides, and interference of gene expression via short interfering RNAs (siRNAs). These antisense-based mechanisms can tackle several genetic disorders in a gene-specific manner, primarily by gene downregulation (gapmers and siRNAs) or splicing defects correction (exon-skipping oligos). Still, the challenge remains for the repair at the single-nucleotide level. The emerging field of epitranscriptomics and RNA modifications shows the enormous possibilities for recoding the transcriptome and repairing genetic mutations with high specificity while harnessing endogenously expressed RNA processing machinery. Some of these techniques have been proposed as alternatives to CRISPR-based technologies, where the exogenous gene-editing machinery needs to be delivered and expressed in the human cells to generate permanent (DNA) changes with unknown consequences. Here, we review the current FDA-approved antisense MoA (emphasizing some enabling technologies that contributed to their success) and three novel modalities based on post-transcriptional RNA modifications with therapeutic potential, including ADAR (Adenosine deaminases acting on RNA)-mediated RNA editing, targeted pseudouridylation, and 2′-O-methylation.

scholarly journals Critical Roles of N6-Methyladenosine (m6A) in Cancer and Virus Infection

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1071 ◽  
Author(s):  
Ken Asada ◽  
Amina Bolatkan ◽  
Ken Takasawa ◽  
Masaaki Komatsu ◽  
Syuzo Kaneko ◽  
...  
Keyword(s):  
Virus Infection ◽  
Cancer Biology ◽  
Viral Infections ◽  
Regulation Of Gene Expression ◽  
Rna Modification ◽  
Integrated Analysis ◽  
Biological Functions ◽  
Rna Modifications ◽  
Long Time ◽  
Epigenetic Analysis

Studies have shown that epigenetic abnormalities are involved in various diseases, including cancer. In particular, in order to realize precision medicine, the integrated analysis of genetics and epigenetics is considered to be important; detailed epigenetic analysis in the medical field has been becoming increasingly important. In the epigenetics analysis, DNA methylation and histone modification analyses have been actively studied for a long time, and many important findings were accumulated. On the other hand, recently, attention has also been focused on RNA modification in the field of epigenetics; now it is known that RNA modification is associated with various biological functions, such as regulation of gene expression. Among RNA modifications, functional analysis of N6-methyladenosine (m6A), the most abundant RNA modification found from humans to plants is actively progressing, and it has also been known that m6A abnormality is involved in cancer and other diseases. Importantly, recent studies have shown that m6A is related to viral infections. Considering the current world situation under threat of viral infections, it is important to deepen knowledge of RNA modification from the viewpoint of viral diseases. Hence, in this review, we have summarized the recent findings regarding the roles of RNA modifications in biological functions, cancer biology, and virus infection, particularly focusing on m6A in mRNA.

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 Immunotherapeutic Potential of m6A-Modifiers in Controlling Acute Myeloid Leukemia

2021 ◽  
Author(s):  
Sunil Kumar ◽  
Ravinder Nagpal ◽  
Amit Kumar ◽  
Muhammad Umer Ashraf ◽  
Yong-Soo Bae
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Therapeutic Potential ◽  
White Blood Cells ◽  
Rna Modification ◽  
Epigenetic Alterations ◽  
Hematopoietic Stem ◽  
Abnormal Accumulation ◽  
Acute Myeloid

Epigenetic alterations have contributed greatly to human carcinogenesis. Conventional epigenetic studies have been predominantly focused on DNA methylation, histone modifications and chromatin remodelling. However, recently, RNA modification (m6A-methylation) also termed ‘epitranscriptomics’ has emerged as a new layer of epigenetic regulation due to its diverse role in various biological processes. In this review, we have summarized the therapeutic potential of m6A-modifiers in controlling haematological disorders especially acute myeloid leukemia (AML). It is a type of blood cancer affecting specific subsets of blood-forming hematopoietic stem/progenitor cells (HSPCs) which proliferate rapidly and acquire self-renewable capacities with impaired terminal cell-differentiation and apoptosis leading to abnormal accumulation of white blood cells, and thus an alternative therapeutic approach is required urgently. Here, we have described how RNA m6A-modification machineries EEE (Editor/writer: Mettl3, Mettl14; Eraser/remover: FTO, ALKBH5 and Effector/reader: YTHDF-1/2) could be reformed into potential druggable candidate or as RNA modifying drug (RMD) to treat leukemia. Moreover, we have shed-light on the role of microRNA and suppressor of cytokine signalling (SOCS/CISH) in increasing anti-tumor immunity towards leukemia. We anticipate, our investigation will provide a fundamental knowledge in nurturing the potential of RNA modifiers in discovering novel therapeutics or immunotherapeutic procedures.

From Ocean to Bedside: the Therapeutic Potential of Molluscan Hemocyanins

2018 ◽  
Vol 25 (20) ◽  
pp. 2292-2303 ◽  
Author(s):  
Negar Talaei Zanjani ◽  
Monica Miranda Saksena ◽  
Fariba Dehghani ◽  
Anthony L. Cunningham
Keyword(s):  
Antiviral Activity ◽  
Clinical Efficacy ◽  
Mechanism Of Action ◽  
Therapeutic Agent ◽  
Marine Invertebrates ◽  
Therapeutic Potential ◽  
Biological Functions ◽  
Anticancer Properties ◽  
Mechanistic Understanding

Hemocyanins are large and versatile glycoproteins performing various immunological and biological functions in many marine invertebrates including arthropods and molluscs. This review discusses the various pharmacological applications of mollusc hemocyanin such as antiviral activity, immunostimulatory and anticancer properties that have been reported in the literature between the years 2000 and 2016. Emphasis is placed on a better mechanistic understanding of hemocyanin as a therapeutic agent. Elucidation of the mechanism of action is essential to improve the clinical efficacy and for a better understanding of some endogenous immunological functions of this complex glycoprotein.

Phytosomal Curcumin Elicits Anti-tumor Properties Through Suppression of Angiogenesis, Cell Proliferation and Induction of Oxidative Stress in Colorectal Cancer

2019 ◽  
Vol 24 (39) ◽  
pp. 4626-4638 ◽  
Author(s):  
Reyhaneh Moradi-Marjaneh ◽  
Seyed M. Hassanian ◽  
Farzad Rahmani ◽  
Seyed H. Aghaee-Bakhtiari ◽  
Amir Avan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Therapeutic Potential ◽  
Vegf Signaling ◽  
Anticancer Effects ◽  
Inhibition Of Angiogenesis ◽  
Underlying Mechanisms ◽  
Apoptotic Activity

Background: Colorectal cancer (CRC) is one of the most common causes of cancer-associated mortality in the world. Anti-tumor effect of curcumin has been shown in different cancers; however, the therapeutic potential of novel phytosomal curcumin, as well as the underlying molecular mechanism in CRC, has not yet been explored. Methods: The anti-proliferative, anti-migratory and apoptotic activity of phytosomal curcumin in CT26 cells was assessed by MTT assay, wound healing assay and Flow cytometry, respectively. Phytosomal curcumin was also tested for its in-vivo activity in a xenograft mouse model of CRC. In addition, oxidant/antioxidant activity was examined by DCFH-DA assay in vitro, measurement of malondialdehyde (MDA), Thiol and superoxidedismutase (SOD) and catalase (CAT) activity and also evaluation of expression levels of Nrf2 and GCLM by qRT-PCR in tumor tissues. In addition, the effect of phytosomal curcumin on angiogenesis was assessed by the measurement of VEGF-A and VEGFR-1 and VEGF signaling regulatory microRNAs (miRNAs) in tumor tissue. Results: Phytosomal curcumin exerts anti-proliferative, anti-migratory and apoptotic activity in-vitro. It also decreases tumor growth and augmented 5-fluorouracil (5-FU) anti-tumor effect in-vivo. In addition, our data showed that induction of oxidative stress and inhibition of angiogenesis through modulation of VEGF signaling regulatory miRNAs might be underlying mechanisms by which phytosomal curcumin exerted its antitumor effect. Conclusion: Our data confirmed this notion that phytosomal curcumin administrates anticancer effects and can be used as a complementary treatment in clinical settings.

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