Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5' sites.
By Schraga Schwartz, Maxwell R Mumbach, M. Jovanović, Timothy C. Wang, K. Maciag, G. G. Bushkin, Philipp Mertins, Dmitry Ter-Ovanesyan, Naomi Habib, D. Cacchiarelli and 10 more. Cell Reports, 2014
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N6-methyladenosine (m6A) is a common modification of mRNA with potential roles in fine-tuning the RNA life cycle. Here, we identify a dense network of proteins interacting with METTL3, a component of the methyltransferase complex, and show that three of them (WTAP, METTL14, and KIAA1429) are required for methylation. Monitoring m6A levels upon WTAP depletion allowed the definition of accurate and near single-nucleotide resolution methylation maps and their classification into WTAP-dependent and -independent sites. WTAP-dependent sites are located at internal positions in transcripts, topologically static across a variety of systems we surveyed, and inversely correlated with mRNA stability, consistent with a role in establishing "basal" degradation rates. WTAP-independent sites form at the first transcribed base as part of the cap structure and are present at thousands of sites, forming a previously unappreciated layer of transcriptome complexity. Our data shed light on the proteomic and transcriptional underpinnings of this RNA modification.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/bac0a89f4e3988e99b2871f513510d5b508d98e0
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Citations in the corpus
- A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation (2015, methodology): “…m6A peak-calling data Data from the previous m6A publications were downloaded directly from the NCBI Gene Expression Omnibus (GEO) and aligned to the same reference genomes byTopHat/Bowtie according to Meyer et al. (2012) and Batista et al. (2014) for mm9 and Schwartz et al. (2014) for hg19.”
- RMBase v2.0: deciphering the map of RNA modifications from epitranscriptome sequencing data (2017, background): “To locate the m6A modification sites in a genome, we predicted the exact m6A positions from the m6A-seq or MeRIP-Seq peaks by searching for consensus RRACH motifs (where R denotes A or G and H denotes A, C or U) (18,30) among the 13 species.”
- m6A RNA methylation: from mechanisms to therapeutic potential (2021, positive): “Depletion of METTL3 homologs leads to defective meiosis in yeast, and developmental arrest in flies and plants (Zhong et al , 2008; Hongay & Orr-Weaver, 2011; Agar-wala et al , 2012; Bodi et al , 2012; Schwartz et al , 2014).”
- Zc3h13 regulates nuclear RNA m6A methylation and mouse embryonic stem cell self-renewal (2018, background): “In Zc3h13 kd mESCs, the m6A/A level decreased by about 60%–70% compared with wild type cells, similar to the level of reduction when WTAP or Virilizer was knocked down in human A549 cells (Schwartz et al., 2014).”
- Rethinking m6A Readers, Writers, and Erasers (2017, methodology): “Shortly after these seminal discoveries, the WTAP-METTL3 interaction was confirmed in diverse mammalian cells (Liu et al. 2014, Ping et al. 2014, Schwartz et al. 2014b).”
- A Unified Model for the Function of YTHDF Proteins in Regulating m6A-Modified mRNA (2020, methodology): “Since m6A mRNAs are known to have a short half-life (2 to 4 h) (Geula et al., 2015; Ke et al., 2017; Schwartz et al., 2014), m6A mRNA expressions are often substantially reduced even at 2 h after actinomycin D treatment.”