m6A RNA modification controls cell fate transition in mammalian embryonic stem cells

By Pedro J. Batista, B. Molinie, Jinkai Wang, Kun Qu, Jiajing Zhang, Lingjie Li, D. Bouley, Ernesto Lujan, Bahareh Haddad, Kaveh Daneshvar and 10 more. Cell Stem Cell, 2014

1,111 citations recorded by the source corpus.

SUMMARY N6-methyl-adenosine (m6A) is the most abundant modification on messenger RNAs and is linked to human diseases, but its functions in mammalian development are poorly understood. Here we reveal the evolutionary conservation and function of m6A by mapping the m6A methylome in mouse and human embryonic stem cells. Thousands of messenger and long noncoding RNAs show conserved m6A modification, including transcripts encoding core pluripotency transcription factors. m6A is enriched over 3′ untranslated regions at defined sequence motifs, and marks unstable transcripts, including transcripts turned over upon differentiation. Genetic inactivation or depletion of mouse and human Mettl3, one of the m6A methylases, led to m6A erasure on select target genes, prolonged Nanog expression upon differentiation, and impaired ESC’s exit from self-renewal towards differentiation into several lineages in vitro and in vivo. Thus, m6A is a mark of transcriptome flexibility required for stem cells to differentiate to specific lineages.

Subfields: Electrical and Electronic Engineering, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/38055711e369a67bd0d8310e897ffcaafda15714

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In Electrical and Electronic Engineering

1. Chuan He
2. P. He
3. Samie R. Jaffrey

In Molecular Biology

1. Chuan He
2. Samie R. Jaffrey
3. P. He
4. Kate D. Meyer
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Citations in the corpus

• Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA (2016, methodology): “These results suggest that the mutated adenosine residue was a target for methylation, which was consistent with the identification of this site by others using m6A immunoprecipitation and RNA sequencing in ESCs (29).”
• FMRP Modulates Neural Differentiation through m6A-Dependent mRNA Nuclear Export (2019, neutral): “The emerging biological functions regulated by m 6 A include the proliferation and differentiation of embryonic (Batista et al., 2014; Geula et al., 2015) and neural stem cells (Wang et al., 2018; Yoon et al., 2017), as well as complex behaviors and processes such as circadian rhythms (Fustin et…”
• Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation (2017, background): “For example, Mettl3 or Mettl14 knockdown reduces m6A levels and decreases self-renewal of primed mouse embryonic stem cells (mESCs) (Wang et al., 2014a), whereas Mettl3 knockout naïve mESCs exhibit improved self-renewal and impaired differentiation, due to dysregulated decay of m6A-tagged transcript”
• The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation (2020, background): “Increasing studies uncover that m6A modification is implicated in diverse biological processes including tissue development, embryonic stem cell self-renewal, and fate determination (7,11,12).”
• Zc3h13 regulates nuclear RNA m6A methylation and mouse embryonic stem cell self-renewal (2018, methodology): “Previous studies of Mettl3 or Mettl14 in mESCs indicate that regulation of mRNA m6A is crucial for mESC self-renewal and differentiation (Batista et al., 2014; Geula et al., 2015; Wang et al., 2014b).”
• RNA modifications modulate gene expression during development (2018, positive): “Examination of gene expression from these embryos and depletion of Mettl3 in embryonic stem cells (ESCs) further suggested impaired exit from pluripotency as, for example, expression of the pluripotency factor Nanog was sustained ( 4, 17 ).”
• The role of m6A RNA methylation in cancer metabolism (2022, background): “4% adenylate residues, especially at the beginning of 3’-UTR near the translation stop codon, the common sequence 5’-RRACH-3’ is usually embedded [16, 17].”
• A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation (2015, methodology): “…m6A-IP to that of the input to calculate the m6A-IP enrichment value. m6A peak region calling Similar to previous m6A studies (Meyer et al. 2012; Batista et al. 2014), we searched for the enrichedm6Apeak regions by scanning the genome using 20-nt sliding windows and evaluating the stat- istical…”
• m6A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells (2017, methodology): “RNA modifications have been implicated in embryonic stem cell maintenance and differentiation (Batista et al., 2014; Wang et al., 2014; Geula et al., 2015), circadian rhythm modification (Fustin et al., 2013), heat shock response (Zhou et al., 2015), meiotic progression (Schwartz et al., 2013), and…”