Mettl3–Mettl14 methyltransferase complex regulates the quiescence of adult hematopoietic stem cells

Yao, Qi; Sang, Lina; Lin, Meixia; Yin, Xiu-Juan; Dong, Wenjie; Gong, Yuping; Zhou, Bo

doi:10.1038/s41422-018-0062-2

Cited by 89 publications

(80 citation statements)

References 13 publications

(12 reference statements)

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“…METTL3 modulates hematopoietic stem cells (HSC) self-renewal through enhancing expressions of selfrenewal-related genes such as Nr4a2, p21, Bmi-1 and Prdm16 [45]. Depletion of METTL3 leads to a significant suppression of HSC reconstitution potential [46].…”

Section: Mettl3mentioning

confidence: 99%

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Functions of N6-methyladenosine and its role in cancer

et al. 2019

Mol Cancer

916

816

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N6-methyladenosine (m6A) is methylation that occurs in the N6-position of adenosine, which is the most prevalent internal modification on eukaryotic mRNA. Accumulating evidence suggests that m6A modulates gene expression, thereby regulating cellular processes ranging from cell self-renewal, differentiation, invasion and apoptosis. M6A is installed by m6A methyltransferases, removed by m6A demethylases and recognized by reader proteins, which regulate of RNA metabolism including translation, splicing, export, degradation and microRNA processing. Alteration of m6A levels participates in cancer pathogenesis and development via regulating expression of tumor-related genes like BRD4, MYC, SOCS2 and EGFR. In this review, we elaborate on recent advances in research of m6A enzymes. We also highlight the underlying mechanism of m6A in cancer pathogenesis and progression. Finally, we review corresponding potential targets in cancer therapy.

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Section: Mettl3mentioning

confidence: 99%

“…METTL14 mediates the self-renewal capabilities of HSCs through promoting the expression of self-renewalrelated genes such as Bmi-1 and Prdm16 [45].…”

Section: Mettl14mentioning

confidence: 99%

Functions of N6-methyladenosine and its role in cancer

et al. 2019

Mol Cancer

916

816

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“…Although validation of Cas9-guide RNA-mediated repression of METTL3 catalytic activity and expression is required for interpretation of the observation, the result suggests an m 6 A-independent function for the "writers" in mouse hematopoiesis. In the Mettl3 and Mettl14 Mx1-Cre-mediated conditional KO mouse models, deletion of Mettl3 (Mettl3Δ/Δ) and Mettl14 (Mettl14Δ/Δ) both decreased global m 6 A levels in adult bone marrow cells, albeit loss of METTL3 conferred a more severe reduction (73). Noticeably, only METTL3, not METTL14, depletion resulted in increased hematopoietic stem cell (HSC) frequency.…”

Section: Erasersmentioning

confidence: 99%

“…Ablation of METTL3 expression in leukemia cells delayed onset of disease in mice. In another study, METTL3 and its catalytic activity was found to be essential in AML through two CRIPSR screens: genome-wide dropout screens and a domain-targeted screen for RNA modifying enzymes using MLL-AF9 FLT3 ITD mouse leukemia cells (73). Depletion of METTL3 results in cell-cycle arrest, differentiation of leukemic cells, and delayed leukemogenesis in vivo.…”

Section: The Role Of M 6 a In Malignant Hematopoiesismentioning

confidence: 99%

The Biology of m6A RNA Methylation in Normal and Malignant Hematopoiesis

2019

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Hematopoietic development and differentiation are highly regulated processes, and recent studies focusing on m 6 A mRNA methylation have uncovered how this mark controls cell fate in both normal and malignant hematopoietic states. In this review, we focus on how writers, readers, and erasers of RNA methylation can mediate distinct phenotypes on mRNAs and on cells. Targeting the RNA methylation program has emerged as a potential novel therapeutic strategy, and we explore the role for these regulators in both normal and dysregulated cell contexts. Signifi cance: RNA methylation is required for cancer cell survival in solid tumors and in acute myeloid leukemia, and targeting this pathway has been proposed as a new therapeutic strategy in cancer. However, understanding the role for RNA methylation in both normal and malignant states is essential for understanding the potential consequences for therapeutic intervention.

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“…In cell-based models, m 6 A has been shown to participate in numerous types of mRNA regulation, including pre-mRNA processing 17,20,21 , mRNA translation efficiency 22 , mRNA stability 16 , and miRNA biogenesis 23 . In the context of hematopoiesis, m 6 A has recently been found to regulate the expansion and self-renewal of hematopoietic stem cells 24,25 , as well as functioning as a negative regulator of myelopoiesis and a potential driver of acute myeloid leukemia (AML) 11,26 .…”

Section: Mainmentioning

confidence: 99%

N⁶-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis

Kuppers

Arora

Lim

et al. 2018

Preprint

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Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we performed a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits were genes coding for the N 6 -methyladenosine (m 6 A) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We found that m 6 A MTase activity promotes erythroid gene expression programs and lineage specification through selective translation of >200 m 6 A marked mRNAs, including those coding for SETD methyltransferase, ribosome, and polyA RNA binding proteins. Remarkably, loss of m 6 A marks resulted in dramatic loss of H3K4me3 across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m 6 A MTase subunit and a subset of their mRNAs targets, including BRD7, CXXC1, PABPC1, PABPC4, STK40, and TADA2B, were required for erythroid specification. Thus, m 6 A mRNA marks promote the translation of a network of genes required for human erythropoiesis.

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Mettl3–Mettl14 methyltransferase complex regulates the quiescence of adult hematopoietic stem cells

Cited by 89 publications

References 13 publications

Functions of N6-methyladenosine and its role in cancer

Functions of N6-methyladenosine and its role in cancer

The Biology of m6A RNA Methylation in Normal and Malignant Hematopoiesis

N⁶-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis

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Mettl3–Mettl14 methyltransferase complex regulates the quiescence of adult hematopoietic stem cells

Cited by 89 publications

References 13 publications

Functions of N6-methyladenosine and its role in cancer

Functions of N6-methyladenosine and its role in cancer

The Biology of m6A RNA Methylation in Normal and Malignant Hematopoiesis

N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis

Contact Info

Product

Resources

About

N⁶-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis