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Nature. 2016 Apr 21;532(7599):329-33. doi: 10.1038/nature17640. Epub 2016 Mar 30.

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

Author information

1
Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut 06520, USA.
2
Pacific Biosciences, 1380 Willow Road, Menlo Park, California 94025, USA.
3
Environmental Sciences &Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
4
Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
5
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
6
Yale Stem Cell Center and Department of Cell Biology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
7
Department of Molecular Biophysics &Biochemistry, Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut 06520, USA.

Abstract

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.

PMID:
27027282
PMCID:
PMC4977844
DOI:
10.1038/nature17640
[Indexed for MEDLINE]
Free PMC Article

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