METTL3-Dependent N6-Methyladenosine Modification Programs Human Neural Progenitor Cell Proliferation

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Nov 14

PMID 37958523

Authors

Yuan Zhao

Jianguo Li

Yilin Lian

Qian Zhou

Yukang Wu

Jiuhong Kang

Affiliations

Soon will be listed here.

Abstract

METTL3, a methyltransferase responsible for N6-methyladenosine (mA) modification, plays key regulatory roles in mammal central neural system (CNS) development. However, the specific epigenetic mechanisms governing human CNS development remain poorly elucidated. Here, we generated small-molecule-assisted shut-off (SMASh)-tagged hESC lines to reduce METTL3 protein levels, and found that METTL3 is not required for human neural progenitor cell (hNPC) formation and neuron differentiation. However, METTL3 deficiency inhibited hNPC proliferation by reducing expression. Mechanistic studies revealed that METTL3 degradation in hNPCs significantly decreased the enrichment of mA in mRNA, consequently reducing its expression. Our findings reveal a novel functional target (SLIT2) for METTL3 in hNPCs and contribute to a better understanding of mA-dependent mechanisms in hNPC proliferation.

Citing Articles

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Yu X, Zhao W, Liu Y, Lv J, Zhong X, Huang P Int J Med Sci. 2024; 21(12):2272-2284.

PMID: 39310263 PMC: 11413893. DOI: 10.7150/ijms.97682.

References

Boyer L, Lee T, Cole M, Johnstone S, Levine S, Zucker J . Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005; 122(6):947-56. PMC: 3006442. DOI: 10.1016/j.cell.2005.08.020. View

Zhao S, Shen Y, Li Q, He Y, Zhang Y, Hu L . SLIT2/ROBO1 axis contributes to the Warburg effect in osteosarcoma through activation of SRC/ERK/c-MYC/PFKFB2 pathway. Cell Death Dis. 2018; 9(3):390. PMC: 5844886. DOI: 10.1038/s41419-018-0419-y. View

Wu Z, Shi Y, Lu M, Song M, Yu Z, Wang J . METTL3 counteracts premature aging via m6A-dependent stabilization of MIS12 mRNA. Nucleic Acids Res. 2020; 48(19):11083-11096. PMC: 7641765. DOI: 10.1093/nar/gkaa816. View

Cao Y, Zhuang Y, Chen J, Xu W, Shou Y, Huang X . Dynamic effects of Fto in regulating the proliferation and differentiation of adult neural stem cells of mice. Hum Mol Genet. 2019; 29(5):727-735. DOI: 10.1093/hmg/ddz274. View

Biteau B, Jasper H . Slit/Robo signaling regulates cell fate decisions in the intestinal stem cell lineage of Drosophila. Cell Rep. 2014; 7(6):1867-75. PMC: 4086754. DOI: 10.1016/j.celrep.2014.05.024. View

Chambers S, Fasano C, Papapetrou E, Tomishima M, Sadelain M, Studer L . Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009; 27(3):275-80. PMC: 2756723. DOI: 10.1038/nbt.1529. View

Bond A, Ming G, Song H . Adult Mammalian Neural Stem Cells and Neurogenesis: Five Decades Later. Cell Stem Cell. 2015; 17(4):385-95. PMC: 4683085. DOI: 10.1016/j.stem.2015.09.003. View

Hall J, Guo G, Wray J, Eyres I, Nichols J, Grotewold L . Oct4 and LIF/Stat3 additively induce Krüppel factors to sustain embryonic stem cell self-renewal. Cell Stem Cell. 2009; 5(6):597-609. DOI: 10.1016/j.stem.2009.11.003. View

Buchman J, Tseng H, Zhou Y, Frank C, Xie Z, Tsai L . Cdk5rap2 interacts with pericentrin to maintain the neural progenitor pool in the developing neocortex. Neuron. 2010; 66(3):386-402. DOI: 10.1016/j.neuron.2010.03.036. View

10.

Zeng C, Huang W, Li Y, Weng H . Roles of METTL3 in cancer: mechanisms and therapeutic targeting. J Hematol Oncol. 2020; 13(1):117. PMC: 7457244. DOI: 10.1186/s13045-020-00951-w. View

11.

Liu W, Xie H, Liu X, Xu S, Cheng S, Wang Z . PQBP1 regulates striatum development through balancing striatal progenitor proliferation and differentiation. Cell Rep. 2023; 42(3):112277. DOI: 10.1016/j.celrep.2023.112277. View

12.

Zhang Z, Wang M, Xie D, Huang Z, Zhang L, Yang Y . METTL3-mediated N-methyladenosine mRNA modification enhances long-term memory consolidation. Cell Res. 2018; 28(11):1050-1061. PMC: 6218447. DOI: 10.1038/s41422-018-0092-9. View

13.

Zhao Y, Wang T, Zhang Y, Shi L, Zhang C, Zhang J . Coordination of EZH2 and SOX2 specifies human neural fate decision. Cell Regen. 2021; 10(1):30. PMC: 8421500. DOI: 10.1186/s13619-021-00092-6. View

14.

Chen J, Zhang Y, Huang C, Shen H, Sun B, Cheng X . mA Regulates Neurogenesis and Neuronal Development by Modulating Histone Methyltransferase Ezh2. Genomics Proteomics Bioinformatics. 2019; 17(2):154-168. PMC: 6620265. DOI: 10.1016/j.gpb.2018.12.007. View

15.

Su Z, Zhang Y, Liao B, Zhong X, Chen X, Wang H . Antagonism between the transcription factors NANOG and OTX2 specifies rostral or caudal cell fate during neural patterning transition. J Biol Chem. 2018; 293(12):4445-4455. PMC: 5868256. DOI: 10.1074/jbc.M117.815449. View

16.

Botquin V, Hess H, Fuhrmann G, Anastassiadis C, Gross M, Vriend G . New POU dimer configuration mediates antagonistic control of an osteopontin preimplantation enhancer by Oct-4 and Sox-2. Genes Dev. 1998; 12(13):2073-90. PMC: 316977. DOI: 10.1101/gad.12.13.2073. View

17.

Ramirez F, Ryan D, Gruning B, Bhardwaj V, Kilpert F, Richter A . deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 2016; 44(W1):W160-5. PMC: 4987876. DOI: 10.1093/nar/gkw257. View

18.

Geula S, Moshitch-Moshkovitz S, Dominissini D, AlFatah Mansour A, Kol N, Salmon-Divon M . Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science. 2015; 347(6225):1002-6. DOI: 10.1126/science.1261417. View

19.

Tao Y, Zhang S . Neural Subtype Specification from Human Pluripotent Stem Cells. Cell Stem Cell. 2016; 19(5):573-586. PMC: 5127287. DOI: 10.1016/j.stem.2016.10.015. View

20.

Yao Y, Yang Y, Guo W, Xu L, You M, Zhang Y . METTL3-dependent mA modification programs T follicular helper cell differentiation. Nat Commun. 2021; 12(1):1333. PMC: 7910450. DOI: 10.1038/s41467-021-21594-6. View