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

N6 -methyladenosine (m 6 A) is the most prevalent and internal modification that occurs in the messenger RNAs (mRNA) of most eukaryotes, although its functional relevance remained a mystery for decades. This modification is installed by the m 6 A methylation "writers" and can be reversed by demethylases that serve as "erasers." In this review, we mainly summarize recent progress in the study of the m 6 A mRNA methylation machineries across eukaryotes and discuss their newly uncovered biological functions. The broad roles of m 6 A in regulating cell fates and embryonic development highlight the existence of another layer of epigenetic regulation at the RNA level, where mRNA is subjected to chemical modifications that affect protein expression.

Summary In mammalian cells, DNA methylation on the 5th position of cytosine (5mC) plays an important role as an epigenetic mark. However, DNA methylation was considered to be absent in C. elegans because of the lack of detectable 5mC as well as homologs of the cytosine DNA methyltransferases. Here, using multiple approaches, we demonstrate the presence of adenine N6-methylation (6mA) in C. elegans DNA. We further demonstrate that this modification increases trans-generationally in a paradigm of epigenetic inheritance. Importantly, we identify a DNA demethylase, NMAD-1, and a potential DNA methyltransferase, DAMT-1, which regulate 6mA levels and crosstalk between methylation of histone H3K4me2 and 6mA, and control the epigenetic inheritance of phenotypes associated with the loss of the H3K4me2 demethylase spr-5. Together, these data identify a DNA modification in C. elegans and raise the exciting possibility that 6mA may be a carrier of heritable epigenetic information in eukaryotes.