DNA methylation on N6-adenine in mammalian embryonic stem cells

Tao P. Wu, Tao Wang, Matthew G. Seetin, Yongquan Lai, Shijia Zhu, Kaixuan Lin, Yifei Liu, Stephanie D. Byrum, Samuel G. Mackintosh, Mei Zhong, Alan Tackett, Guilin Wang, Lawrence S. Hon, Gang Fang, James A. Swenberg and Andrew Z. Xiao ()
Additional contact information
Tao P. Wu: Yale School of Medicine
Tao Wang: Yale School of Medicine
Matthew G. Seetin: Pacific Biosciences
Yongquan Lai: Environmental Sciences & Engineering, University of North Carolina at Chapel Hill
Shijia Zhu: Icahn School of Medicine at Mount Sinai
Kaixuan Lin: Yale School of Medicine
Yifei Liu: Yale School of Medicine
Stephanie D. Byrum: University of Arkansas for Medical Sciences, Little Rock
Samuel G. Mackintosh: University of Arkansas for Medical Sciences, Little Rock
Mei Zhong: Yale School of Medicine
Alan Tackett: University of Arkansas for Medical Sciences, Little Rock
Guilin Wang: Yale Center for Genome Analysis, Yale School of Medicine
Lawrence S. Hon: Pacific Biosciences
Gang Fang: Icahn School of Medicine at Mount Sinai
James A. Swenberg: Environmental Sciences & Engineering, University of North Carolina at Chapel Hill
Andrew Z. Xiao: Yale School of Medicine

Nature, 2016, vol. 532, issue 7599, 329-333

Abstract: Abstract 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 ( 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.

Date: 2016
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DOI: 10.1038/nature17640

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