4.6 Review

N6-methyladenosine-mediated gene regulation and therapeutic implications

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Article Immunology

YTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8+ T cells

Shoubao Ma et al.

Summary: Caligiuri and colleagues demonstrate that the m(6)A reader YTHDF2 controls the inflammatory activation and antitumor function of tumor-associated macrophages by regulating the stability of Stat1 mRNA. They show that YTHDF2 deficiency in TAMs reprograms them towards an antitumoral phenotype, enhancing their antigen cross-presentation ability and CD8(+) T cell-mediated antitumor immunity. Moreover, targeting YTHDF2 in TAMs using a Toll-like receptor 9 agonist-conjugated small interfering RNA restrains tumor growth and improves the efficacy of PD-L1 antibody therapy. These findings suggest that YTHDF2 inhibition is a promising strategy to enhance cancer immunotherapy.

NATURE IMMUNOLOGY (2023)

Review Cell Biology

3′UTR heterogeneity and cancer progression

Jia Jia Chan et al.

Summary: The majority of human mRNAs generate alternative 3' UTRs through various processes, including RNA editing, m6A methylation, and alternative polyadenylation (APA), with 3' UTR splicing as an emerging mechanism. Regulation of these processes at the genome and transcriptome levels contribute to 3' UTR heterogeneity. Genomic variants in 3' UTR regions and aberrant 3' UTR processing are associated with cancer and their deregulation may contribute to cancer pathogenesis. In-depth characterization of these events will enhance our understanding of their significance and aid in therapeutic development.

TRENDS IN CELL BIOLOGY (2023)

Article Biotechnology & Applied Microbiology

Absolute quantification of single-base m6A methylation in the mammalian transcriptome using GLORI

Cong Liu et al.

Summary: In this study, a method called GLORI was developed to quantify the m(6)A modification. GLORI is an unbiased and convenient method that can provide absolute quantification of the m(6)A methylome. The study reveals clustered m(6)A modifications with differential distribution and stoichiometry in mouse and human cells.

NATURE BIOTECHNOLOGY (2023)

Article Oncology

The RNA m6A Reader YTHDF1 Is Required for Acute Myeloid Leukemia Progression

Yun-Guang Hong et al.

Summary: N-6-methyladenosine (m(6)A) has been identified as a crucial modulator in acute myelogenous leukemia (AML). The overexpression of YTHDF1, an m(6)A reader protein, in AML samples, especially in leukemia stem cells, promotes AML progression. Depletion of YTHDF1 attenuates self-renewal, proliferation, and leukemic capacity of AML cells and can be targeted by the FDA-approved drug tegaserod. Tegaserod inhibits the binding of YTHDF1 with m(6)A-modified mRNAs and reduces AML cell viability in vitro and prolongs survival in xenograft models.

CANCER RESEARCH (2023)

Review Biochemistry & Molecular Biology

m6A modification: recent advances, anticancer targeted drug discovery and beyond

Li-Juan Deng et al.

Summary: Abnormal N6-methyladenosine (m6A) modification is closely related to cancer development, and finding targeted anticancer drugs is important. Traditional herbs and computer-synthesized compounds are reasonable sources for these drugs. Artificial intelligence has advantages in discovering m6A-targeting anticancer drugs.

MOLECULAR CANCER (2022)

Article Chemistry, Multidisciplinary

Glutathione-Bioimprinted Nanoparticles Targeting of N6-methyladenosine FTO Demethylase as a Strategy against Leukemic Stem Cells

Kunxia Cao et al.

Summary: In this study, FTO inhibitor-loaded GSH-bioimprinted nanocomposites were developed to selectively target leukemia cells, especially leukemia stem cells (LSCs), and induce cell death by disrupting intracellular redox status. Additionally, the nanocomposites increased m(6)A RNA modification levels and enhanced the efficacy of immune therapy.
Editorial Material Biochemistry & Molecular Biology

Domain confusion 2: m6A-independent role of YTHDC2

Simone Larivera et al.

Summary: The study reveals that YTHDC2 interacts with U-rich motifs and functions independently of m6A through its unique DExD helicase domain in spermatogenesis of mice and fish.

MOLECULAR CELL (2022)

Article Biochemistry & Molecular Biology

Dynamic control of chromatin-associated m6A methylation regulates nascent RNA synthesis

Wenqi Xu et al.

Summary: The METTL3/METTL14/WTAP m(6)A methyltransferase complex is responsible for depositing m(6)A modification on nascent transcripts from promoters and enhancers, protecting them from premature termination by the Integrator complex and promoting productive transcription.

MOLECULAR CELL (2022)

Article Cell Biology

UPF1 promotes rapid degradation of m6A-containing RNAs

Sung Ho Boo et al.

Summary: This study reveals the interaction between UPF1 and YTHDF2, leading to rapid degradation of m(6)A RNAs. UPF1 mediates the degradation of m(6)A RNAs through a specific interaction with the N-terminal residues of YTHDF2 and interaction with PNRC2. Transcriptome-wide analyses show that mRNAs bound to YTHDF2 undergo destabilization with a higher dependency on UPF1. These findings highlight the dynamic and multilayered regulation of m(6)A RNA stability and the multifaceted role of UPF1 in mRNA decay.

CELL REPORTS (2022)

Article Oncology

The m6A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia

Hengyou Weng et al.

Summary: This study reveals the oncogenic role of IGF2BP2 and the critical role of m(6)A modification in AML. Inhibiting IGF2BP2 may be a promising therapeutic strategy for AML.

CANCER CELL (2022)

Article Biochemistry & Molecular Biology

Nuclear m6A reader YTHDC1 suppresses proximal alternative polyadenylation sites by interfering with the 3′ processing machinery

Liutao Chen et al.

Summary: The N6-methyladenosine (m(6)A) modification and alternative polyadenylation (APA) are important regulators of gene expression. YTHDC1, an m(6)A reader, was found to suppress proximal APA sites and produce longer 3' UTR transcripts by binding to upstream m(6)A sites. The interaction between YTHDC1 and FIP1L1, as well as the liquid-liquid phase separation promoted by m(6)A binding, may play a crucial role in APA regulation.

EMBO REPORTS (2022)

Article Cell Biology

RBM45 is an m6A-binding protein that affects neuronal differentiation and the splicing of a subset of mRNAs

Seung H. Choi et al.

Summary: RBM45, an m(6)A-binding protein, plays a crucial role in controlling mRNA processing and neuronal differentiation by recognizing methylated RNA during brain development.

CELL REPORTS (2022)

Article Cell Biology

Cryo-EM structures of human m6A writer complexes

Shichen Su et al.

Summary: This study reveals the structure and function of the m(6)A writer complex. Cryo-EM and other experimental methods were used to uncover the structure of MACOM and its interaction with MAC.

CELL RESEARCH (2022)

Article Biochemistry & Molecular Biology

ALKBH5/MAP3K8 axis regulates PD-L1+macrophage infiltration and promotes hepatocellular carcinoma progression

Yu You et al.

Summary: ALKBH5 is highly expressed in hepatocellular carcinoma (HCC) and is associated with worse prognosis. It promotes the proliferation and metastasis of HCC cells and recruits macrophages through the ALKBH5/MAP3K8 axis, thus promoting HCC growth and metastasis.

INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES (2022)

Review Oncology

FTO in cancer: functions, molecular mechanisms, and therapeutic implications

Yangchan Li et al.

Summary: N-6-methyladenosine (m(6)A) is the most abundant internal modification in mRNA that affects RNA processing, stability, and translation. The fat mass and obesity-associated protein (FTO), discovered as the first RNA m(6)A demethylase, is frequently dysregulated and plays important roles in various types of cancers. Targeting FTO holds promising therapeutic significance via suppressing tumor growth, potentiating immunotherapy, and attenuating drug resistance.

TRENDS IN CANCER (2022)

Article Cell Biology

m6A modification promotes miR-133a repression during cardiac development and hypertrophy via IGF2BP2

Benheng Qian et al.

Summary: The study revealed that m6A modification facilitates the repression of specific miRNA, particularly miR-133a, during cardiac development and hypertrophy through a precise regulatory mechanism involving the AGO2-IGF2BP2 complex. Targeting m6A modification could potentially provide a strategy to counteract hypertrophic gene expression induced by miR-133a.

CELL DEATH DISCOVERY (2021)

Article Biochemistry & Molecular Biology

m6A-RNA Demethylase FTO Inhibitors Impair Self-Renewal in Glioblastoma Stem Cells

Sarah Huff et al.

Summary: N-6-methyladenosine (m(6)A) is the most abundant mRNA modification that regulates gene expression and plays a key role in various diseases. The FTO inhibitor FTO-04 has been shown to effectively inhibit neurosphere formation in glioblastoma stem cells, making it a potential new lead for treating glioblastoma.

ACS CHEMICAL BIOLOGY (2021)

Review Biochemistry & Molecular Biology

m6A RNA methylation: from mechanisms to therapeutic potential

P. Cody He et al.

Summary: m(6)A, the most prevalent mRNA modification, regulates gene expression by influencing mRNA metabolism in various physiological and pathophysiological processes. It plays a multifaceted role in mRNA decay, translation, and transcription, highlighting its crucial importance in post-transcriptional gene expression regulation.

EMBO JOURNAL (2021)

Review Oncology

The role of IGF2BP2, an m6A reader gene, in human metabolic diseases and cancers

Jinyan Wang et al.

Summary: IGF2BP2 is an RNA-binding protein that regulates cellular metabolism and cancer development by post-transcriptional regulation. It is also an independent prognostic factor for multiple cancer types.

CANCER CELL INTERNATIONAL (2021)

Article Biochemistry & Molecular Biology

N(6)-methyladenosine-binding protein YTHDF1 suppresses EBV replication and promotes EBV RNA decay

Tian-Liang Xia et al.

Summary: This study demonstrates that EBV transcripts exhibit differential m(6)A modification in human NPC biopsies and cells at different infection stages, and the m(6)A-modified EBV transcripts are recognized and destabilized by the YTHDF1 protein, leading to suppression of EBV infection and replication. YTHDF1 accelerates viral RNA decapping and mediates RNA decay, thereby downregulating the expression of EBV genes post-transcriptionally.

EMBO REPORTS (2021)

Article Multidisciplinary Sciences

METTL3 regulates heterochromatin in mouse embryonic stem cells

Wenqi Xu et al.

Summary: METTL3 regulates mouse embryonic stem-cell heterochromatin, critical for silencing retroviral elements and mammalian development. Through m(6)A methylation, METTL3 modulates integrity of IAP heterochromatin.

NATURE (2021)

Article Multidisciplinary Sciences

The RNA m6A reader YTHDC1 silences retrotransposons and guards ES cell identity

Jiadong Liu et al.

Summary: The study reveals that the m(6)A RNA modification and YTHDC1 play essential roles in regulating retrotransposons and cellular reprogramming during early mouse embryonic development.

NATURE (2021)

Review Pharmacology & Pharmacy

Liquid-liquid phase separation: a principal organizer of the cell's biochemical activity architecture

Jason Z. Zhang et al.

Summary: Numerous processes in cells occur simultaneously, with liquid-liquid phase separation being a key mechanism that impacts the organization of cellular processes, especially in signaling pathways. Advancements in research tools have helped us gain a better understanding of the functional impact of phase separation on biochemical processes.

TRENDS IN PHARMACOLOGICAL SCIENCES (2021)

Article Multidisciplinary Sciences

Dynamic regulation of N6,2′-O-dimethyladenosine (m6Am) in obesity

Moshe Shay Ben-Haim et al.

Summary: The study highlights the dynamic role of m(6)Am in obesity-related translation regulation, with findings showing elevated FTO levels in obese mice and downregulation of genes losing m(6)Am marking, including FABP2 and FABP5. Furthermore, the enrichment of m(6)Am-methylated genes in metabolic processes was observed, and the association of m(6)Am methylation with increased mRNA stability, translation efficiency, and higher protein expression was unequivocally demonstrated through Mettl3 knockout.

NATURE COMMUNICATIONS (2021)

Article Biochemistry & Molecular Biology

Splice site m6A methylation prevents binding of U2AF35 to inhibit RNA splicing

Mateusz Mendel et al.

Summary: The study reveals that the C. elegans writer METT-10 deposits an m(6)A mark on the SAM synthetase pre-mRNA, inhibiting proper splicing and protein production triggered by a rich diet. Although the mechanism is not present in mammalian SAM synthetase pre-mRNA, splicing inhibition by 3' splice site m(6)A is conserved in mammals.
Article Cell Biology

Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance

Yi Liu et al.

Summary: Research has identified the m(6)A demethylase FTO as a key regulator in tumors, impacting immune surveillance through glycolytic metabolism regulation. Knockdown of FTO impairs tumor cell glycolytic activity, restores CD8(+) T cell function, and inhibits tumor growth. Additionally, the development of the small-molecule compound Dac51 can block FTO-mediated immune evasion and synergize with checkpoint blockade for improved tumor control.

CELL METABOLISM (2021)

Article Multidisciplinary Sciences

Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia

Eliza Yankova et al.

Summary: The study identified a highly potent and selective catalytic inhibitor of METTL3, STM2457, which shows potential therapeutic value in treating AML. Treatment with this inhibitor leads to reduced AML growth, increased differentiation and apoptosis, and decreased m(6)A levels on leukemogenic mRNAs. In vivo pharmacological inhibition of METTL3 results in impaired engraftment and prolonged survival in mouse models of AML.

NATURE (2021)

Article Biochemistry & Molecular Biology

m6A RNA methylation of major satellite repeat transcripts facilitates chromatin association and RNA:DNA hybrid formation in mouse heterochromatin

Katarzyna J. Duda et al.

Summary: Heterochromatin plays essential roles in maintaining chromosome structure, protecting genome integrity, and stabilizing gene expression programs. Recent study reveals that heterochromatic RNA in mouse ES cells is enriched with m6A, a RNA modification crucial for stabilizing mouse heterochromatin.

NUCLEIC ACIDS RESEARCH (2021)

Article Oncology

Loss of m6A demethylase ALKBH5 promotes post-ischemic angiogenesis via post-transcriptional stabilization of WNT5A

Yongchao Zhao et al.

Summary: The study revealed that ALKBH5 acts as a negative regulator in post-ischemic angiogenesis, modulating WNT5A mRNA stability in an m6A-dependent manner. Targeting ALKBH5 may be a potential therapeutic option for ischemic diseases.

CLINICAL AND TRANSLATIONAL MEDICINE (2021)

Article Oncology

The loss of RNA N6-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8+ T cell dysfunction and tumor growth

Lihui Dong et al.

Summary: The study reveals that the m(6)A methyltransferase Mettl14 in TAMs plays a role in modulating the function of CD8(+) T cells by regulating C1q(+) TAMs, ultimately affecting tumor progression.

CANCER CELL (2021)

Article Biochemistry & Molecular Biology

Acute depletion of METTL3 implicates N6-methyladenosine in alternative intron/exon inclusion in the nascent transcriptome

Guifeng Wei et al.

Summary: The m(6)A modification in RNA plays crucial roles in RNA regulation, potentially influencing RNA splicing. The presence of m(6)A peaks in RNA is related to RNA binding sites and histone modifications, and depletion of METTL3 can disrupt RNA splicing, particularly at 5' splice sites. m(6)A can regulate the inclusion of alternative introns/exons and affect the splicing process.

GENOME RESEARCH (2021)

Article Biochemistry & Molecular Biology

m6A RNA methylation regulates promoter-proximal pausing of RNA polymerase II

Junaid Akhtar et al.

Summary: m(6)A RNA modification regulates RNAP II pausing in Drosophila cells, affecting pause release, Ser2P occupancy, and nascent RNA transcription. The m(6)A-mediated gene regulation adds another layer to the control of gene expression.

MOLECULAR CELL (2021)

Article Biochemistry & Molecular Biology

Enhancer RNA m6A methylation facilitates transcriptional condensate formation and gene activation

Joo-Hyung Lee et al.

Summary: The study reveals the heavy but selective deposition of m6A on nascent RNAs produced by transcription regulatory elements, and shows that m6A-eRNAs mark highly active enhancers by recruiting YTHDC1 and promoting condensate formation. This mechanism plays broad roles in enhancer activation and gene transcriptional control.

MOLECULAR CELL (2021)

Article Pharmacology & Pharmacy

Loss of m6A methyltransferase METTL3 promotes heart regeneration and repair after myocardial injury

Rui Gong et al.

Summary: Deficiency of METTL3 promotes cardiomyocyte proliferation and improves cardiac function after myocardial infarction by regulating the miR-143-Yap/Ctnnd1 axis. This study highlights the significance of RNA m(6)A modification in heart regeneration.

PHARMACOLOGICAL RESEARCH (2021)

Article Multidisciplinary Sciences

METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells

Hao Song et al.

Summary: The m(6)A methylation protects the homeostasis and tumor immunosurveillance function of NK cells.

NATURE COMMUNICATIONS (2021)

Article Biochemistry & Molecular Biology

YTHDF2 alleviates cardiac hypertrophy via regulating Myh7 mRNA decoy

Hongfei Xu et al.

Summary: This study reveals that YTHDF2 suppresses cardiac hypertrophy through Myh7 mRNA decoy in an m6A-dependent manner. It underscores the functional importance of YTHDF2-dependent cardiac m6A mRNA regulation during cardiac hypertrophy, and offers a novel mechanistic insight into the therapeutic mechanisms of YTHDF2.

CELL AND BIOSCIENCE (2021)

Article Immunology

The RNA m6A reader YTHDF2 controls NK cell antitumor and antiviral immunity

Shoubao Ma et al.

Summary: The N-6-methyladenosine modification plays a crucial role in NK cell immunity, with YTHDF2 being a key reader; YTHDF2 maintains NK cell homeostasis and function, modulating NK cell survival and proliferation through a positive feedback loop.

JOURNAL OF EXPERIMENTAL MEDICINE (2021)

Article Biochemistry & Molecular Biology

eIF4E3 forms an active eIF4F complex during stresses (eIF4FS) targeting mTOR and re-programs the translatome

Benjamin Weiss et al.

Summary: The eIF4E family of initiation factors regulate protein synthesis by binding to mRNA cap structures. Among them, eIF4E3 is recruited to the translation complex after mTOR inhibition by Torin1, reprogramming the translatome to enhance cellular stress resistance. Its interaction with diverse cellular proteins suggests potential additional functions beyond initiation factor roles.

NUCLEIC ACIDS RESEARCH (2021)

Article Medicine, Research & Experimental

Saikosaponin D exhibits anti-leukemic activity by targeting FTO/m(6)A signaling

Kaiju Sun et al.

Summary: The study revealed that SsD has broad anti-proliferation effects in AML by targeting FTO/m(6)A signaling pathway, increasing global m(6)A RNA methylation levels, and suppressing relevant pathways affecting AML cell proliferation.

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Philippe L Bedard et al.

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Ye Fu et al.

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A Unified Model for the Function of YTHDF Proteins in Regulating m6A-Modified mRNA

Sara Zaccara et al.

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ALKBH5 suppresses malignancy of hepatocellular carcinoma via m6A-guided epigenetic inhibition of LYPD1

Yunhao Chen et al.

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