DNA methylation on N6-adenine in mammalian embryonic stem cells
Open accessAbstract
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.
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Reported differences in 6mA distribution between mouse and human may represent tissue-specific patterns rather than species differences, because the tissues used were unique to each species.
“Reported difference in 6mA distribution between mouse and human may represent tissue specific patterns rather than species differences, since the tissues used for the mouse and human studies were unique to each species (mESC and blood DNA, respectively (60, 61)).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [61]
These findings are supported by the identification of both a methyltransferase and a demethylase for deposition and removal of 6mA.
“These findings are supported by the identification of both methyltransferase and demethylase for deposition and removal of 6mA, respectively (60, 61).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [61]
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- Authors
- Wu, T. P., Wang, T., Seetin, M. G., Lai, Y., Zhu, S., Lin, K., Liu, Y., Byrum, S. D., Mackintosh, S. G., Zhong, M., Tackett, A., Wang, G., Hon, L. S., Fang, G., Swenberg, J. A., & Xiao, A. Z.
- Affiliations
- Yale University (US)
- Pacific Biosciences (United States) (US)
- University of North Carolina at Chapel Hill (US)
- Icahn School of Medicine at Mount Sinai (US)
- University of Arkansas for Medical Sciences (US)
- Corresponding author
- Xiao, Andrew Z.
- ORCID
- Venue
- Nature
- Published
- 2016-03-30
- Volume
- 532
- Issue
- 7599
- Pages
- 329-333
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4977844
- OpenAlex
- W2313190268
- Cited by
- 648
- References
- 41
- Citations by year
- 2026: 19 · 2025: 40 · 2024: 47 · 2023: 68 · 2022: 70 · 2021: 84 · 2020: 69 · 2019: 73 · 2018: 74 · 2017: 68 · 2016: 32 · 2012: 1
- FWCI
- 42.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (1s10od018445-01, UL1TR001863)
- National Cancer Institute (P30CA016359)
- National Institute of General Medical Sciences (P20GM103429, R01GM114205, R01GM106024, R01GM114472)
- National Institute of Environmental Health Sciences (P42ES005948, P30ES010126)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Keywords
- N6-methyladenine, DNA methylation, ALKBH1, demethylases, epigenetic silencing, mouse embryonic stem cells, X chromosome inactivation, enhancer silencing, embryonic stem cell differentiation, epigenetic regulation
- MeSH terms
- Mouse Embryonic Stem Cells, AlkB Homolog 1, Histone H2a Dioxygenase, Adenine, Animals, Cell Differentiation, DNA Transposable Elements, Enhancer Elements, Genetic, Mammals, X Chromosome, Up-Regulation, Evolution, Molecular, DNA Methylation, Long Interspersed Nucleotide Elements, Gene Silencing, DNA-(Apurinic or Apyrimidinic Site) Lyase, Epigenesis, Genetic, Mice
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