title: The KRAB-ZFP/KAP1 system contributes to the early embryonic establishment of site-specific DNA methylation patterns maintained during development.
abstract: De novo DNA methylation is an essential aspect of the epigenetic reprogramming that takes place during early development, yet factors responsible for its instatement at particular genomic loci are poorly defined. Here, we demonstrate that the KRAB-ZFP-mediated recruitment of KAP1 to DNA in embryonic stem cells (ESCs) induces cytosine methylation. This process is preceded by H3K9 trimethylation, and genome-wide analyses reveal that it spreads over short distances from KAP1-binding sites so as to involve nearby CpG islands. In sharp contrast, in differentiated cells, KRAB/KAP1-induced heterochromatin formation does not lead to DNA methylation. Correspondingly, the methylation status of CpG islands in the adult mouse liver correlates with their proximity to KAP1-binding sites in ESCs, not in hepatocytes. Therefore, KRAB-ZFPs and their cofactor KAP1 are in part responsible for the establishment during early embryogenesis of site-specific DNA methylation patterns that are maintained through development.
authors.affiliation: School of Life Sciences and Frontiers in Genetics Program, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Quenneville
authors.forename: Priscilla
authors.initials: P
authors.lastname: Turelli
authors.forename: Karolina
authors.initials: K
authors.lastname: Bojkowska
authors.forename: Charlène
authors.initials: C
authors.lastname: Raclot
authors.forename: Sandra
authors.initials: S
authors.lastname: Offner
authors.forename: Adamandia
authors.initials: A
authors.lastname: Kapopoulou
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
mesh_terms: D000818:Animals; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D047108:Embryonic Development; D053595:Embryonic Stem Cells / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D000076183:Tripartite Motif-Containing Protein 28; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D002843:Chromatin; D006657:Histones; D009687:Nuclear Proteins; D012097:Repressor Proteins; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28; D044767:Ubiquitin-Protein Ligases; C117054:Uhrf1 protein, mouse; C486788:Zfp472 protein, mouse