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A METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation


N6-methyladenosine (m6A) is the most prevalent and reversible internal modification in mammalian messenger and noncoding RNAs. We report here that human methyltransferase-like 14 (METTL14) catalyzes m6A RNA methylation. Together with METTL3, the only previously known m6A methyltransferase, these two proteins form a stable heterodimer core complex of METTL3–METTL14 that functions in cellular m6A deposition on mammalian nuclear RNAs. WTAP, a mammalian splicing factor, can interact with this complex and affect this methylation.

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Figure 1: METTL3, METTL14 and WTAP affect the cellular m6A level in polyadenylated RNA with METTL3 and METTL14 forming a stable complex.
Figure 2: In vitro methylation activity of METTL3, METTL14 and WTAP.
Figure 3: Identification of RNA-binding sites of METTL3 and METTL14 and a schematic illustration for nuclear RNA N6-adenosine methylation.

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This study was supported by US National Institutes of Health (GM071440 and GM088599). We thank P. Faber and L. Dore for helping with high-throughput sequencing experiments and S.F. Reichard for editing the manuscript.

Author information

Authors and Affiliations



C.H. conceived the project. J.L. and Y.Y. designed and performed most experiments. D.H. and Z.L. performed high-throughput sequencing data analyses. X.W. and Y.F. helped perform the PAR-CLIP experiment, biochemistry assay and data analysis. L.Z. and M.Y. assisted in expressing recombinant proteins in insect cells. G.J. and W.C. participated in subcloning. X.D. participated in nuclear extract separation. Q.D. synthesized the d3-m6A standard for LC/MS/MS analysis. J.L., Y.Y. and C.H. wrote the manuscript.

Corresponding author

Correspondence to Chuan He.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Figures 1–15, Supplementary Tables 1–12 and Supplementary Notes 1–4. (PDF 3479 kb)

Supplementary Data Set 1

Summary of METTL3 target genes based on 4SU-PAR-CLIP (XLSX 298 kb)

Supplementary Data Set 2

Summary of METTL14 target genes based on 4SU-PAR-CLIP (XLSX 202 kb)

Supplementary Data Set 3

Summary of WTAP target genes based on 4SU-PAR-CLIP (XLSX 312 kb)

Supplementary Data Set 4

Summary of m6A peaks that show statistically significant decrease in the m6A-IP/input ratio upon METTL3 knockdown (P < 0.05) (XLSX 137 kb)

Supplementary Data Set 5

Summary of m6A peaks that show statistically significant decrease in the m6A-IP/input ratio upon METTL14 knockdown (P < 0.05) (XLSX 45 kb)

Supplementary Data Set 6

Summary of m6A peaks that show statistically significant decrease in the m6A-IP/input ratio upon WTAP knockdown (P < 0.05) (XLSX 48 kb)

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Liu, J., Yue, Y., Han, D. et al. A METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol 10, 93–95 (2014).

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