Fox Family Protein Jumu Reads 6mA-DNA Codes and Contributes to Zygotic Gene Activation

N6-methyladenine (6mA) DNA modification in eukaryotic genomes has emerged as a potential epigenetic mark. However, little is known about how 6mA epigenetic codes are read and interpreted in higher eukaryotes. Here we investigate 6mA genome-wide distributions in multiple higher eukaryotes. UsingDrosophilaas a pioneer system, we show that 6mA exhibits defined patterns and preferentially marks zygotic genes in early embryos. Moreover, we identify that the Fox-family protein, Jumu, is a "6mA-DNA reader" and functions in concert with DMAD to contribute to zygotic gene activation. Further methylome analysis reveals that 6mA modification has common features in genomic DNA from mouse, rat and monkey, and that "forkhead-domain-binding motifs" are enriched in 6mA-marked DNA of these genomes, in a way similar to Drosophila. Collectively, our findings identify the 6mA DNA reader protein and suggest a conserved 6mA-based mechanism in higher eukaryotes.N6-甲基腺嘌呤（N6-methyladenine，6mA）在真核基因组中的DNA修饰已成为一类潜在的表观遗传标记。然而，目前对于高等真核生物中6mA表观遗传密码的读取与解读机制仍知之甚少。本研究针对多种高等真核生物开展全基因组范围的6mA分布特征分析。以果蝇（Drosophila）作为模式研究系统，我们发现6mA呈现出明确的分布模式，且优先标记早期胚胎中的合子基因。此外，本研究鉴定出叉头框（Fox）家族蛋白Jumu为一类“6mA-DNA读取蛋白”，其可与DMAD协同发挥功能，参与合子基因激活过程。进一步的甲基化组分析显示，小鼠、大鼠与猴的基因组DNA中的6mA修饰具有共同特征，且这些物种基因组中被6mA标记的DNA区域富集有“叉头结构域结合基序（forkhead-domain-binding motifs）”，该特征与果蝇中的情况高度相似。综上，本研究鉴定出6mA DNA读取蛋白，并揭示了高等真核生物中基于6mA的保守调控机制。