Loss of YTHDF2-mediated m6A-dependent mRNA clearance facilitates hematopoietic stem cell regeneration

Wang, Hu; Zuo, Hongna; Liu, Jin; Wen, Fei; Gao, Yawei; Zhu, Xudong; Liu, Bo; Xiao, Feng; Wang, Wengong; Huang, Gang; Shen, Bin; Ju, Zhenyu

doi:10.1038/s41422-018-0082-y

Cited by 103 publications

(91 citation statements)

References 10 publications

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“…Among which, YTHDF2 is the first identified and the most extensively studied m6A reader. YTHDF2 can bind to m6A residues located in the untranslated region through C-terminal YTD domain and render the targeted mRNA to processing bodies for subsequent degradation [35,36]. Unlike YTHDF2, YTHDF1 promotes mRNA translation efficiency by interacting with EIF3 to promote rate-limiting step of translation for m6A-modified mRNAs [37].…”

Section: Discussionmentioning

confidence: 99%

METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST

et al. 2020

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Background: N6-methyladenosine (m6A) is the most prevalent RNA epigenetic regulation in eukaryotic cells. However, understanding of m6A in colorectal cancer (CRC) is very limited. We designed this study to investigate the role of m6A in CRC.Methods: Expression level of METTL14 was extracted from public database and tissue array to investigate the clinical relevance of METTL14 in CRC. Next, gain/loss of function experiment was used to define the role of METTL14 in the progression of CRC. Moreover, transcriptomic sequencing (RNA-seq) was applied to screen the potential targets of METTL14. The specific binding between METTL14 and presumed target was verified by RNA pull-down and RNA immunoprecipitation (RIP) assay. Furthermore, rescue experiment and methylated RNA immunoprecipitation (Me-RIP) were performed to uncover the mechanism.Results: Clinically, loss of METTL14 correlated with unfavorable prognosis of CRC patients. Functionally, knockdown of METTL14 drastically enhanced proliferative and invasive ability of CRC cells in vitro and promoted tumorigenicity and metastasis in vivo. Mechanically, RNA-seq and Me-RIP identified lncRNA XIST as the downstream target of METTL14. Knockdown of METTL14 substantially abolished m6A level of XIST and augmented XIST expression. Moreover, we found that m6A-methylated XIST was recognized by YTHDF2, a m6A reader protein, to mediate the degradation of XIST. Consistently, XIST expression negatively correlated with METTL14 and YTHDF2 in CRC tissues.Conclusion: Our findings highlight the function and prognostic value of METTL14 in CRC and extend the understanding of the importance of RNA epigenetics in cancer biology.

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Section: Discussionmentioning

confidence: 99%

METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST

et al. 2020

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“…Recent studies have shown that loss of YTHDF2 results in enhancement of hematopoietic stem cell expansion in both mouse and human [21,22]. In contrast, depletion of YTHDF2 in AML resulted in apoptosis of AML cells [23].…”

Section: Ythdf2 Stability Is Maintained By Cdk1mentioning

confidence: 99%

“…Likewise, Ythdf2 was confirmed maternally essential for early zygotic development in mice [19], and Ythdf2 depletion also negatively impacts the proliferation and differentiation of neural progenitor cells in mouse [20], suggesting broad impact of Ythdf2 on mRNA degradation in different tissues and cell types in vertebrates. The significant role of YTHDF2 in cell differentiation was further shown with depletion of YTHDF2-blocking differentiation and driving self-renewal of both mouse and human hematopoietic stem cells [21,22]. This protein is also critical to acute myeloid leukemia (AML) [23].…”

Section: Introductionmentioning

confidence: 98%

YTHDF2 promotes mitotic entry and is regulated by cell cycle mediators

et al. 2020

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The N 6 -methyladenosine (m 6 A) modification regulates mRNA stability and translation. Here, we show that transcriptomic m 6 A modification can be dynamic and the m 6 A reader protein YTH N 6 -methyladenosine RNA binding protein 2 (YTHDF2) promotes mRNA decay during cell cycle. Depletion of YTHDF2 in HeLa cells leads to the delay of mitotic entry due to overaccumulation of negative regulators of cell cycle such as Wee1-like protein kinase (WEE1). We demonstrate that WEE1 transcripts contain m 6 A modification, which promotes their decay through YTHDF2. Moreover, we found that YTHDF2 protein stability is dependent on cyclin-dependent kinase 1 (CDK1) activity. Thus, CDK1, YTHDF2, and WEE1 form a feedforward regulatory loop to promote mitotic entry. We further identified Cullin 1 (CUL1), Cullin 4A (CUL4A), damaged DNA-binding protein 1 (DDB1), and S-phase kinase-associated protein 2 (SKP2) as components of E3 ubiquitin ligase complexes that mediate YTHDF2 proteolysis. Our study provides insights into how cell cycle mediators modulate transcriptomic m 6 A modification, which in turn regulates the cell cycle.

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“…In consequence, YTHDF2 inhibitor is considered as a candidate strategy for AML treatment. A noteworthy phenomenon in biological condition is that YTHDF2 mediates clearance of m 6 A-modified mRNAs of Wntrelated genes to suppress Wnt signaling at stable state and maintain HSC quiescence (79). Upon hematological stresses, downregulation of YTHDF2 aberrantly upregulates target genes of Wnt signaling as well as survival-associated genes, which elevates not only proliferation but also regeneration capacity of HSCs synergistically, as a protective measure.…”

Section: Ythdf2mentioning

confidence: 99%

“…For instance, competitive antagonists inhibiting ALKBH5 over other AlkB subfamily proteins such as FTO could possibly reduce the enrichment of BCSCs and impair their ability to initiate breast tumor (62). Nevertheless, m 6 A regulatory enzymes might exert distinct impact on stem cells in physiological and pathological conditions as mentioned above (42,43,69,73,79). It is plausible to put forward that the m 6 A-targeted strategy in CSCs must be conducted on the premise of distinguishing the normal stem cells from CSCs.…”

Section: Clinical Relevance Of M 6 A-targeted Strategymentioning

confidence: 99%

N6-Methyladenosine: A Novel RNA Imprint in Human Cancer

Liu

et al. 2019

Front. Oncol.

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N 6 -Methyladenosine (m 6 A), a pervasive posttranscriptional modification which is reversible, has been among hotspot issues in the past several years. The balance of intracellular m 6 A levels is dynamically maintained by methyltransferase complex and demethylases. Meanwhile, m 6 A reader proteins specifically recognize modified residues and convey messages so as to set up an efficient and orderly network of m 6 A regulation. The m 6 A mark has proved to affect every step of RNA life cycle, from processing in nucleus to translation or degradation in cytoplasm. Subsequently, disorders in m 6 A methylation are directly related to aberrant RNA metabolism, which results in tumorigenesis and altered drug response. Therefore, uncovering the underlying mechanism of m 6 A in oncogenic transformation and tumor progression seeks opportunities for novel targets in cancer therapy. In this review, we conclude the extensive impact of m 6 A on RNA metabolism and highlight its relevance with human cancer, implicating the far-reaching value in clinical application.

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Loss of YTHDF2-mediated m6A-dependent mRNA clearance facilitates hematopoietic stem cell regeneration

Cited by 103 publications

References 10 publications

METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST

METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST

YTHDF2 promotes mitotic entry and is regulated by cell cycle mediators

N6-Methyladenosine: A Novel RNA Imprint in Human Cancer

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