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. Using Drosophila as 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. Overall design: SMRTseq data of DMAD knock down fly head mRNA profiles of different stages (0.75h, 3h, 6h), DMAD knockdown( dsRNA(DMAD) ), Jumu knockdown( dsRNA(DMAD) ) and control ( dsRNA(GFP) ) embryos were generated by deep sequencing, using Illumina Hiseq2500. Different stages and tissues of four species 6mA were generated by deep sequencing, using Illumina Hiseq2500.