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In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions

Quenneville, Simon; Verde, Gaetano; Corsinotti, Andrea; Kapopoulou, Adamandia; Jakobsson, Johan LU ; Offner, Sandra; Baglivo, Ilaria; Pedone, Paolo V; Grimaldi, Giovanna and Riccio, Andrea, et al. (2011) In Molecular Cell 44(3). p.72-361
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... (More)

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.

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@article{0a8e6d4a-ba68-4997-abf3-002c05edd0b0,
  abstract     = {<p>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.</p>},
  author       = {Quenneville, Simon and Verde, Gaetano and Corsinotti, Andrea and Kapopoulou, Adamandia and Jakobsson, Johan and Offner, Sandra and Baglivo, Ilaria and Pedone, Paolo V and Grimaldi, Giovanna and Riccio, Andrea and Trono, Didier},
  issn         = {1097-4164},
  keyword      = {Animals,Base Sequence,Binding Sites,Cell Line,Chromatin Assembly and Disassembly,Chromosomal Proteins, Non-Histone,DNA Methylation,DNA Modification Methylases,Embryonic Stem Cells,Gene Expression Regulation, Developmental,Gene Knockout Techniques,Genomic Imprinting,Histone-Lysine N-Methyltransferase,Mice,Mice, Inbred C57BL,Molecular Sequence Data,Nuclear Proteins,Nucleotide Motifs,Protein Methyltransferases,Repressor Proteins,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {11},
  number       = {3},
  pages        = {72--361},
  publisher    = {Cell Press},
  series       = {Molecular Cell},
  title        = {In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions},
  url          = {http://dx.doi.org/10.1016/j.molcel.2011.08.032},
  volume       = {44},
  year         = {2011},
}