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METTL16 has recently been identified as an RNA methyltransferase responsible for the deposition of N⁶-methyladenosine (m⁶A) in a few transcripts. Whether METTL16 methylates a large set of transcripts, similar to METTL3 and METTL14, remains unclear. Here we show that METTL16 exerts both methyltransferase activity-dependent and -independent functions in gene regulation. In the cell nucleus, METTL16 functions as an m⁶A writer to deposit m⁶A into hundreds of its specific messenger RNA targets. In the cytosol, METTL16 promotes translation in an m⁶A-independent manner. More specifically, METTL16 directly interacts with the eukaryotic initiation factors 3a and -b as well as ribosomal RNA through its Mtase domain, thereby facilitating the assembly of the translation-initiation complex and promoting the translation of over 4,000 mRNA transcripts. Moreover, we demonstrate that METTL16 is critical for the …