title: In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions.
abstract: The maintenance of H3K9 and DNA methylation at imprinting control regions (ICRs) during early embryogenesis is key to the regulation of imprinted genes. Here, we reveal that ZFP57, its cofactor KAP1, and associated effectors bind selectively to the H3K9me3-bearing, DNA-methylated allele of ICRs in ES cells. KAP1 deletion induces a loss of heterochromatin marks at ICRs, whereas deleting ZFP57 or DNMTs leads to ICR DNA demethylation. Accordingly, we find that ZFP57 and KAP1 associated with DNMTs and hemimethylated DNA-binding NP95. Finally, we identify the methylated TGCCGC hexanucleotide as the motif that is recognized by ZFP57 in all ICRs and in several tens of additional loci, several of which are at least ZFP57-dependently methylated in ES cells. These results significantly advance our understanding of imprinting and suggest a general mechanism for the protection of specific loci against the wave of DNA demethylation that affects the mammalian genome during early embryogenesis.
authors: School of Life Sciences and Frontiers in Genetics Program, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors: Simon
authors: S
authors: Quenneville
authors: Gaetano
authors: G
authors: Verde
authors: Andrea
authors: A
authors: Corsinotti
authors: Adamandia
authors: A
authors: Kapopoulou
authors: Johan
authors: J
authors: Jakobsson
authors: Sandra
authors: S
authors: Offner
authors: Ilaria
authors: I
authors: Baglivo
authors: Paolo V
authors: PV
authors: Pedone
authors: Giovanna
authors: G
authors: Grimaldi
authors: Andrea
authors: A
authors: Riccio
authors: Didier
authors: D
authors: Trono
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D018392:Genomic Imprinting; D011495:Histone-Lysine N-Methyltransferase; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D059372:Nucleotide Motifs; D011496:Protein Methyltransferases / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000076183:Tripartite Motif-Containing Protein 28; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D002868:Chromosomal Proteins, Non-Histone; D009687:Nuclear Proteins; D012097:Repressor Proteins; C501529:Zfp-57 protein, mouse; D015254:DNA Modification Methylases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C516239:SETDB1 protein, mouse; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28; D044767:Ubiquitin-Protein Ligases; C117054:Uhrf1 protein, mouse