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, Andrew Z. Xiao

Research output: Contribution to journalArticle

184 Citations (Scopus)

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 (<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.

Original languageEnglish (US)
Pages (from-to)329-333
Number of pages5
JournalNature
Volume532
Issue number7599
DOIs
StatePublished - Apr 21 2016
Externally publishedYes

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Adenine
DNA Methylation
Embryonic Stem Cells
Epigenomics
Transcriptional Activation
Long Interspersed Nucleotide Elements
Genome
5-Methylcytosine
X-Linked Genes
X Chromosome
Cell Differentiation
DNA
Genes

ASJC Scopus subject areas

  • General

Cite this

Wu, T. P., Wang, T., Seetin, M. G., Lai, Y., Zhu, S., Lin, K., ... Xiao, A. Z. (2016). DNA methylation on N6-adenine in mammalian embryonic stem cells. Nature, 532(7599), 329-333. https://doi.org/10.1038/nature17640

DNA methylation on N6-adenine in mammalian embryonic stem cells. / 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.

In: Nature, Vol. 532, No. 7599, 21.04.2016, p. 329-333.

Research output: Contribution to journalArticle

Wu, TP, Wang, T, Seetin, MG, Lai, Y, Zhu, S, Lin, K, Liu, Y, Byrum, SD, Mackintosh, SG, Zhong, M, Tackett, A, Wang, G, Hon, LS, Fang, G, Swenberg, JA & Xiao, AZ 2016, 'DNA methylation on N6-adenine in mammalian embryonic stem cells', Nature, vol. 532, no. 7599, pp. 329-333. https://doi.org/10.1038/nature17640
Wu TP, Wang T, Seetin MG, Lai Y, Zhu S, Lin K et al. DNA methylation on N6-adenine in mammalian embryonic stem cells. Nature. 2016 Apr 21;532(7599):329-333. https://doi.org/10.1038/nature17640
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. / DNA methylation on N6-adenine in mammalian embryonic stem cells. In: Nature. 2016 ; Vol. 532, No. 7599. pp. 329-333.
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