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 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 le...

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Bibliographic Details
Published in:Nature (London) 2016-03, Vol.532 (7599), p.329-333
Main Authors: Wu, Tao P., Wang, Tao, Seetin, Matthew G., Lai, Yongquan, Zhu, Shijia, Lin, Kaixuan, Liu, Yifei, Byrum, Stephanie D., Mackintosh, Samuel G., Zhong, Mei, Tackett, Alan, Wang, Guilin, Hon, Lawrence S., Fang, Gang, Swenberg, James A., Xiao, Andrew Z.
Format: Article
Language:English
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Summary: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 (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.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature17640