title: DNA methylation on N(6)-adenine in mammalian embryonic stem cells.
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.
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Tao P
authors.initials: TP
authors.lastname: Wu
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Pacific Biosciences, 1380 Willow Road, Menlo Park, California 94025, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Seetin
authors.affiliation: Environmental Sciences &Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Lai
authors.affiliation: 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.
authors.forename: Shijia
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Kaixuan
authors.initials: K
authors.lastname: Lin
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Byrum
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Mackintosh
authors.affiliation: Yale Stem Cell Center and Department of Cell Biology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhong
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Tackett
authors.affiliation: Department of Molecular Biophysics &Biochemistry, Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Guilin
authors.initials: G
authors.lastname: Wang
authors.affiliation: Pacific Biosciences, 1380 Willow Road, Menlo Park, California 94025, USA.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Hon
authors.affiliation: 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.
authors.forename: Gang
authors.initials: G
authors.lastname: Fang
authors.affiliation: Environmental Sciences &Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
authors.affiliation: Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Andrew Z
authors.initials: AZ
authors.lastname: Xiao
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism; D000071498:AlkB Homolog 1, Histone H2a Dioxygenase; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019175:DNA Methylation; D004251:DNA Transposable Elements / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D019143:Evolution, Molecular; D020868:Gene Silencing; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008322:Mammals / Q000235:genetics; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D014960:X Chromosome / Q000235:genetics / Q000378:metabolism
chemical_list: D000225:Adenine; D000071498:AlkB Homolog 1, Histone H2a Dioxygenase; D004251:DNA Transposable Elements; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C529511:Alkbh1 protein, mouse; C000730567:6-methyladenine