N6-methyladenosine (m6A) has been demonstrated to be ubiquitous in several types of eukaryotic RNAs, including messenger RNA (mRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), long non-coding RNA (lncRNA), and small nuclear RNA (snRNA)[1]. The recent discoveries of RNA m6A methyltransferase complex METTL3/METTL14/WTAP and demethylases FTO and ALKBH5 prove the reversibility of m6A modification [2-6]. This modification plays important roles in various biological processes, including circadian rhythms [7], RNA splicing [8], yeast meiosis [9], and embryonic stem cell self-renewal [10]. Two recent studies show that YTH domain family 2 (YTHDF2) and other YTHDF proteins preferentially bind to m6A-containing mRNA in vivo and in vitro and regulate localization and stability of the bound mRNA [8, 11]. YTHDF2 is also known to be involved in development of acute myeloid leukemia [12]. YTHDC1 (splicing factor YT521-B), another YTH domain-containing protein, is known to play an important role in Emery-Dreifuss muscular dystrophy. While the function of YTHDF2 in the regulation of mRNA stability has been explored, the molecular mechanism for specific recognition of m6A by the YTH domain remains elusive. YTHDF2 consists of a C-terminal YTH domain (designated as YTHYTHDF2), which specifically binds to m6A-containing RNA (m6A-RNA) with a preference for those containing a consensus motif of G (m6A) C [11]. The YTH domains are highly conserved in YTH domain-containing proteins, including YTHDF1-3, YTHDC1, YTHDC2 (CsA-associated helicase-like protein),