title: CpG islands recruit a histone H3 lysine 36 demethylase.
abstract: In higher eukaryotes, up to 70% of genes have high levels of nonmethylated cytosine/guanine base pairs (CpGs) surrounding promoters and gene regulatory units. These features, called CpG islands, were identified over 20 years ago, but there remains little mechanistic evidence to suggest how these enigmatic elements contribute to promoter function, except that they are refractory to epigenetic silencing by DNA methylation. Here we show that CpG islands directly recruit the H3K36-specific lysine demethylase enzyme KDM2A. Nucleation of KDM2A at these elements results in removal of H3K36 methylation, creating CpG island chromatin that is uniquely depleted of this modification. KDM2A utilizes a zinc finger CxxC (ZF-CxxC) domain that preferentially recognizes nonmethylated CpG DNA, and binding is blocked when the CpG DNA is methylated, thus constraining KDM2A to nonmethylated CpG islands. These data expose a straightforward mechanism through which KDM2A delineates a unique architecture that differentiates CpG island chromatin from bulk chromatin.
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford, UK.
authors.forename: Neil P
authors.initials: NP
authors.lastname: Blackledge
authors.forename: Jin C
authors.initials: JC
authors.lastname: Zhou
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Tolstorukov
authors.forename: Anca M
authors.initials: AM
authors.lastname: Farcas
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Park
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Klose
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D044783:F-Box Proteins; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D010089:Oxidoreductases, N-Demethylating / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D004268:DNA-Binding Proteins; D044783:F-Box Proteins; D006657:Histones; D011994:Recombinant Proteins; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; D010089:Oxidoreductases, N-Demethylating; D008239:Lysine