July 19, 2019  |  

DNA methylation on N(6)-adenine in mammalian embryonic stem cells.

Authors: Wu, Tao P and Wang, Tao and Seetin, Matthew G and Lai, Yongquan and Zhu, Shijia and Lin, Kaixuan and Liu, Yifei and Byrum, Stephanie D and Mackintosh, Samuel G and Zhong, Mei and Tackett, Alan and Wang, Guilin and Hon, Lawrence S and Fang, Gang and Swenberg, James A and Xiao, Andrew Z

It has been widely accepted that 5-methylcytosine is the only form of DNA methylation in mammalian genomes. Here we identify N(6)-methyladenine as another form of DNA modification in mouse embryonic stem cells. Alkbh1 encodes a demethylase for N(6)-methyladenine. An increase of N(6)-methyladenine levels in Alkbh1-deficient cells leads to transcriptional silencing. N(6)-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 N(6)-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, N(6)-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 N(6)-methyladenine constitutes a crucial component of the epigenetic regulation repertoire in mammalian genomes.

Journal: Nature
DOI: 10.1038/nature17640
Year: 2016

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