Role of RNA modification in gastrointestinal tumors

AbstractAutophagy is a conserved degradation process crucial to maintaining the primary function of cellular and organismal metabolism. Impaired autophagy could develop numerous diseases, including cancer, cardiomyopathy, neurodegenerative disorders, and aging. N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells, and the fate of m6A modified transcripts is controlled by m6A RNA binding proteins. m6A modification influences mRNA alternative splicing, stability, translation, and subcellular localization. Intriguingly, recent studies show that m6A RNA methylation could alter the expression of essential autophagy-related (ATG) genes and influence the autophagy function. Thus, both m6A modification and autophagy could play a crucial role in the onset and progression of various human diseases. In this review, we summarize the latest studies describing the impact of m6A modification in autophagy regulation and discuss the role of m6A modification-autophagy axis in different human diseases, including obesity, heart disease, azoospermatism or oligospermatism, intervertebral disc degeneration, and cancer. The comprehensive understanding of the m6A modification and autophagy interplay may help in interpreting their impact on human diseases and may aid in devising future therapeutic strategies.

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The role of m6A modification in the biological functions and diseases

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00450-x ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Xiulin Jiang ◽

Baiyang Liu ◽

Zhi Nie ◽

Lincan Duan ◽

Qiuxia Xiong ◽

...

Keyword(s):

Cancer Progression ◽

Molecular Mechanisms ◽

Target Genes ◽

Rna Modification ◽

Biological Functions ◽

Rna Methylation ◽

Downstream Target ◽

Different Types ◽

M6a Rna Methylation

AbstractN6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as “readers”. Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

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METTL3-dependent N6-methyladenosine RNA modification mediates the atherogenic inflammatory cascades in vascular endothelium

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2025070118 ◽

2021 ◽

Vol 118 (7) ◽

pp. e2025070118

Author(s):

Chian-Shiu Chien ◽

Julie Yi-Shuan Li ◽

Yueh Chien ◽

Mong-Lien Wang ◽

Aliaksandr A. Yarmishyn ◽

...

Keyword(s):

Blood Flow ◽

Endothelial Activation ◽

Plaque Formation ◽

Rna Modification ◽

Branch Points ◽

Monocyte Adhesion ◽

Down Regulation ◽

Hemodynamic Forces

Atherosclerosis is characterized by the plaque formation that restricts intraarterial blood flow. The disturbed blood flow with the associated oscillatory stress (OS) at the arterial curvatures and branch points can trigger endothelial activation and is one of the risk factors of atherosclerosis. Many studies reported the mechanotransduction related to OS and atherogenesis; however, the transcriptional and posttranscriptional regulatory mechanisms of atherosclerosis remain unclear. Herein, we investigated the role of N6-methyladenosine (m6A) RNA methylation in mechanotransduction in endothelial cells (ECs) because of its important role in epitranscriptome regulation. We have identified m6A methyltransferase METTL3 as a responsive hub to hemodynamic forces and atherogenic stimuli in ECs. OS led to an up-regulation of METTL3 expression, accompanied by m6A RNA hypermethylation, increased NF-κB p65 Ser536 phosphorylation, and enhanced monocyte adhesion. Knockdown of METTL3 abrogated this OS-induced m6A RNA hypermethylation and other manifestations, while METTL3 overexpression led to changes resembling the OS effects. RNA-sequencing and m6A-enhanced cross-linking and immunoprecipitation (eCLIP) experiments revealed NLRP1 and KLF4 as two hemodynamics-related downstream targets of METTL3-mediated hypermethylation. The METTL3-mediated RNA hypermethylation up-regulated NLRP1 transcript and down-regulated KLF4 transcript through YTHDF1 and YTHDF2 m6A reader proteins, respectively. In the in vivo atherosclerosis model, partial ligation of the carotid artery led to plaque formation and up-regulation of METTL3 and NLRP1, with down-regulation of KLF4; knockdown of METTL3 via repetitive shRNA administration prevented the atherogenic process, NLRP3 up-regulation, and KLF4 down-regulation. Collectively, we have demonstrated that METTL3 serves a central role in the atherogenesis induced by OS and disturbed blood flow.

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

Frontiers in Genetics ◽

10.3389/fgene.2021.733871 ◽

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.

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The Role of Protein Arginine Methyltransferase 1 in Gastrointestinal Cancers

10.5772/intechopen.96197 ◽

2021 ◽

Author(s):

Jin Zou ◽

Wei Shen ◽

Yu Zhang ◽

Shibo Ying

Keyword(s):

Tumor Cells ◽

Cancer Progression ◽

Cancer Metastasis ◽

Arginine Methylation ◽

Gastrointestinal Tumors ◽

Migration And Invasion ◽

Arginine Methyltransferase ◽

Tumorigenic Mechanism ◽

Methyltransferase 1

Mammals can produce nine kinds of arginine methylation enzymes that can be divided into three types (I, II, and III) according to their catalytic activity. Arginine methyltransferase 1 (PRMT1), as the first discovered arginine methyltransferase type I, has been reported to be involved in cell signal transduction, DNA damage repair, RNA transcription and other processes. Its imbalance or abnormal expression is also involved in cancer metastasis. PRMT1 is highly expressed in gastrointestinal tumors and promotes tumor biomarkers expression, chemotherapy resistance and tumorigenicity to promote cancer progression, while downregulation of PRMT1 expression can inhibit the migration and invasion of related tumor cells or promote tumor cells apoptosis and inhibit the progression of cancer. Therefore, PRMT1 may be a cancer therapeutic target. In this paper, arginine methylase 1 expression in various types of gastrointestinal tumors, the tumorigenic mechanism and the role of PRMT1 in tumorigenesis and development were reviewed.

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Regulatory Role of N6-methyladenosine (m6A) Modification in Osteosarcoma

Frontiers in Oncology ◽

10.3389/fonc.2021.683768 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yujie Zhang ◽

Yanyan Wang ◽

Liwei Ying ◽

Sifeng Tao ◽

Mingmin Shi ◽

...

Keyword(s):

Molecular Mechanism ◽

Research Trends ◽

Rna Modification ◽

Future Research ◽

Related Factors ◽

The Past ◽

Pathophysiological Role ◽

Primary Bone ◽

Non Coding Rnas

Osteosarcoma is the most common primary bone malignancy, typically occurring in childhood or adolescence. Unfortunately, the clinical outcomes of patients with osteosarcoma are usually poor because of the aggressive nature of this disease and few treatment advances in the past four decades. N6-methyladenosine (m6A) is one of the most extensive forms of RNA modification in eukaryotes found both in coding and non-coding RNAs. Accumulating evidence suggests that m6A-related factors are dysregulated in multiple osteosarcoma processes. In this review, we highlight m6A modification implicated in osteosarcoma, describing its pathophysiological role and molecular mechanism, as well as future research trends and potential clinical application in osteosarcoma.

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Genome wide quantification of A-to-I RNA editing activity

10.21203/rs.2.12827/v1 ◽

2019 ◽

Author(s):

Shalom Hillel Roth ◽

Erez Y. Levanon ◽

Eli Eisenberg

Keyword(s):

Rna Editing ◽

Innate Immune ◽

Rna Modification ◽

Immune Disorders ◽

Computational Tool ◽

Genome Wide ◽

Editing Activity ◽

Single Number ◽

Editing Level

Abstract Adenosine to inosine (A-to-I) RNA editing by the ADAR enzymes is a common RNA modification, preventing false activation of the innate immune system by endogenous dsRNAs. Methods for quantification of ADAR activity are sought after, due to an increasing interest in the role of ADARs in cancer and auto-immune disorders, as well as attempts to harness the ADAR enzymes for RNA engineering. Here we present the Alu Editing Index (AEI), a robust and simple-to-use computational tool devised for this purpose that produces a single number representing the global editing level from BAM files. The AEI tool is available at https://github.com/a2iEditing/RNAEditingIndexer

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Dynamic N6-methyladenosine RNA methylation in brain and diseases

Epigenomics ◽

10.2217/epi-2019-0260 ◽

2020 ◽

Vol 12 (4) ◽

pp. 371-380 ◽

Cited By ~ 1

Author(s):

Andrew M Shafik ◽

Emily G Allen ◽

Peng Jin

Keyword(s):

Brain Development ◽

Rna Modification ◽

Normal Brain ◽

Biological Processes ◽

Future Directions ◽

Body Of Knowledge ◽

Neuropsychiatric Diseases ◽

The Brain ◽

Normal Brain Development

N6-methyladenosine (m6A) is a dynamic RNA modification that regulates various aspects of RNA metabolism and has been implicated in many biological processes and transitions. m6A is highly abundant in the brain; however, only recently has the role of m6A in brain development been a focus. The machinery that controls m6A is critically important for proper neurodevelopment, and the precise mechanisms by which m6A regulates these processes are starting to emerge. However, the role of m6A in neurodegenerative and neuropsychiatric diseases still requires much elucidation. This review discusses and summarizes the current body of knowledge surrounding the function of the m6A modification in regulating normal brain development, neurodegenerative diseases and outlines possible future directions.

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