Late Replication Timing

Several types of heterochromatin, including silenced X chromatin, replicate late in S phase. Genes on the Xa replicate earlier than their counterparts on the Xi (Schmidt and Migeon 1990; Hansen et al. 1993, 1995; Torchia et al. 1994). Analysis of two replicons on the X chromosome showed that the same origins fire both on the Xi and the Xa (Cohen et al. 2003), suggesting that the same origins are differentially regulated on these chromosomes. This study raises an interesting question: What mechanisms are used to direct different behavior of the same origins on two homologous chromosomes within a single nucleus?

Studies in Drosophila may provide insight into the link between replication and silencing. Fly HP1 binds to components of the origin recognition complex (ORC) and flies mutant for an ORC protein show abnormalities in formation of heterochromatin (Pak et al. 1997). The three mammalian HP1 isoforms co-localize with heterochromatic regions, including the heterochro-matin of the Xi (Chadwick and Willard 2003). HP1 is thought to nucleate the spread of heterochromatin by binding methylated H3-K9 and recruiting HMTases to methylate H3-K9 on neighboring nucleosomes. The interaction between HP1 and ORCs suggests two distinct models for the co-regulation of replication and silencing. Late-replicating origins on the Xi may recruit HP1, which mediates silencing. Alternatively, HP1 on the Xi could mediate a change in chromatin structure that affects both gene expression and replication timing.

Late replication timing and DNA methylation on the Xi show an intriguing relationship. Treatment with the DNA-demethylating agent 5-azadeoxycyti-dine can trigger early replication of the Xi and reactivation of X-linked loci (Hansen et al. 1996). In addition, cells deficient in DNMT3b show early replication of reactivated X-linked genes (Hansen et al. 2000). In DNMT3b mutant cells, a number of X-linked genes are unmethylated. A subset of these unmethylated genes replicate early and are expressed, suggesting that DNA methylation can influence replication timing.

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