DNA methylation on N6 adenine in mammalian embryonic stem cells
It has been widely accepted that 5 methylcytosine is the only form of DNA methylation in mammalian genomes. Here we identify N6 methyladenine as another form of DNA modification in mouse embryonic stem cells. Alkbh1 encodes a demethylase for N6 methyladenine. An increase of N6 methyladenine levels in Alkbh1 deficient cells leads to transcriptional silencing. N6 methyladenine deposition is inversely correlated with the evolutionary age of LINE 1 transposons; its deposition is strongly enriched at young <1.5 million years old) but not old >6 million years old) L1 elements. The deposition of N6 methyladenine correlates with epigenetic silencing of such LINE 1 transposons, together with their neighbouring enhancers and genes, thereby resisting the gene activation signals during embryonic stem cell differentiation. As young full length LINE 1 transposons are strongly enriched on the X chromosome, genes located on the X chromosome are also silenced. Thus, N6 methyladenine developed a new role in epigenetic silencing in mammalian evolution distinct from its role in gene activation in other organisms. Our results demonstrate that N6 methyladenine constitutes a crucial component of the epigenetic regulation repertoire in mammalian genomes.
Nature