In Embryonic Stem Cells, ZFP57/KAP1 Recognize a Methylated Hexanucleotide to Affect Chromatin and DNA Methylation of Imprinting Control Regions

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 E...

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Bibliographic Details
Published in:Molecular cell 2011-11, Vol.44 (3), p.361-372
Main Authors: Quenneville, Simon, Verde, Gaetano, Corsinotti, Andrea, Kapopoulou, Adamandia, Jakobsson, Johan, Offner, Sandra, Baglivo, Ilaria, Pedone, Paolo V., Grimaldi, Giovanna, Riccio, Andrea, Trono, Didier
Format: Article
Language:English
Subjects:
alleles
Animals
Base Sequence
Binding Sites
Cell Line
Chromatin
Chromatin Assembly and Disassembly
Chromosomal Proteins, Non-Histone - metabolism
Clonal deletion
Cofactors
Demethylation
DNA
DNA Methylation
DNA Modification Methylases - metabolism
Embryo cells
Embryogenesis
embryonic stem cells
Embryonic Stem Cells - metabolism
Gene Expression Regulation, Developmental
Gene Knockout Techniques
Gene regulation
Genomes
Genomic Imprinting
Heterochromatin
Histone-Lysine N-Methyltransferase
Imprinting
loci
mammals
Mice
Mice, Inbred C57BL
Molecular Sequence Data
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Nucleotide Motifs
Protein Methyltransferases - metabolism
Repressor Proteins - genetics
Repressor Proteins - metabolism
Stem cells
Transcription
Tripartite Motif-Containing Protein 28
Waves
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Summary: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. ► ZFP57/KAP1 bind all methylated imprinted control regions in ES cells ► ZFP57/KAP1 bind other nonimprinted methylated sequences in ES cells ► ZFP57/KAP1 are necessary for DNA and histone methylation maintenance ► ZFP57 recognizes a methylated hexanucleotide with two C2H2 zinc fingers
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2011.08.032