title: The impact of chromatin modifiers on the timing of locus replication in mouse embryonic stem cells.
abstract: BACKGROUND
  The time of locus replication during S-phase is tightly regulated and correlates with chromatin state. Embryonic stem (ES) cells have an unusual chromatin profile where many developmental regulator genes that are not yet expressed are marked by both active and repressive histone modifications. This poised or bivalent state is also characterized by locus replication in early S-phase in ES cells, while replication timing is delayed in cells with restricted developmental options.
  
  
  RESULTS
  Here we used a panel of mutant mouse ES cell lines lacking important chromatin modifiers to dissect the relationship between chromatin structure and replication timing. We show that temporal control of satellite DNA replication is sensitive to loss of a variety of chromatin modifiers, including Mll, Eed, Dnmt1, Suv39h1/h2 and Dicer. The replication times of many single copy loci, including a 5 Mb contiguous region surrounding the Rex1 gene, were retained in chromatin modifier mutant ES cells, although a subset of loci were affected.
  
  
  CONCLUSIONS
  This analysis demonstrates the importance of chromatin modifiers for maintaining correct replication of satellite sequences in pluripotent ES cells and highlights the sensitivity of some single copy loci to the influence of chromatin modifiers. Abundant histone acetylation is shown to correlate well with early replication. Surprisingly, loss of DNA methylation or histone methylation was tolerated by many loci, suggesting that these modifications may be less influential for the timing of euchromatin replication.
authors: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, London W12 0NN, UK. helle.jorgensen@csc.mrc.ac.uk
authors: Helle F
authors: HF
authors: Jørgensen
authors: Véronique
authors: V
authors: Azuara
authors: Shannon
authors: S
authors: Amoils
authors: Mikhail
authors: M
authors: Spivakov
authors: Anna
authors: A
authors: Terry
authors: Tatyana
authors: T
authors: Nesterova
authors: Bradley S
authors: BS
authors: Cobb
authors: Bernard
authors: B
authors: Ramsahoye
authors: Matthias
authors: M
authors: Merkenschlager
authors: Amanda G
authors: AG
authors: Fisher
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D019175:DNA Methylation; D004261:DNA Replication; D004276:DNA, Satellite / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000378:metabolism; D051379:Mice; D009154:Mutation; D016196:S Phase / Q000235:genetics
chemical_list: D002843:Chromatin; D004276:DNA, Satellite; D006657:Histones
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