Publication Date:
2016-03-31
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- P20GM103429/GM/NIGMS NIH HHS/ -- P30 ES010126/ES/NIEHS NIH HHS/ -- P42 ES005948/ES/NIEHS NIH HHS/ -- R01 GM114472-01/GM/NIGMS NIH HHS/ -- R01GM106024/GM/NIGMS NIH HHS/ -- R01GM114205-01/GM/NIGMS NIH HHS/ -- S10OD018445/OD/NIH HHS/ -- England -- Nature. 2016 Apr 21;532(7599):329-33. doi: 10.1038/nature17640. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut 06520, USA. ; Pacific Biosciences, 1380 Willow Road, Menlo Park, California 94025, USA. ; Environmental Sciences &Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ; 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. ; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. ; Yale Stem Cell Center and Department of Cell Biology, Yale School of Medicine, New Haven, Connecticut 06520, USA. ; Department of Molecular Biophysics &Biochemistry, Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27027282" target="_blank"〉PubMed〈/a〉
Keywords:
Adenine/*analogs & derivatives/metabolism
;
Animals
;
Cell Differentiation/genetics
;
*DNA Methylation
;
DNA Transposable Elements/genetics
;
DNA-(Apurinic or Apyrimidinic Site) Lyase/deficiency/genetics/metabolism
;
Enhancer Elements, Genetic/genetics
;
Epigenesis, Genetic/*genetics
;
Evolution, Molecular
;
Gene Silencing
;
Long Interspersed Nucleotide Elements/genetics
;
Mammals/genetics
;
Mice
;
Mouse Embryonic Stem Cells/cytology/*metabolism
;
Up-Regulation/genetics
;
X Chromosome/genetics/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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