Replication timing and transcriptional control: beyond cause and effect—part II
Introduction
In every multi-cellular system examined, early replication and transcription are strongly correlated. This long-standing correlation has recently been confirmed statistically in Drosophila, human, and mouse cells [1, 2, 3, 4, 5, 6, 7•, 8••]. Moreover, an extensive developmental regulation of replication timing was rigorously demonstrated, associated with changes in transcription [8••]. However, progress in understanding the underlying mechanisms remains sluggish. The relationship is clearly indirect, since 10–20% of late-replicating genes are expressed and some genes change transcription without changes in replication timing and vice versa [8••]. The simplest explanation is that replication timing is related to features of chromatin and nuclear architecture rather than transcription per se.
Two genres of models, in which either chromatin dictates replication time or vice versa, were illustrated in a prior review (Figure 1 of [9]) and need no revision. Advances in the intervening years have underscored the complexity and variety of mechanisms by which chromatin can influence replication timing, with most effects surprisingly modest and some paradoxical. Ironically, some of our deepest mechanistic insights have come from budding and fission yeasts, yet there is no evidence for an association between replication timing and transcription in these unicellular organisms [10]. Evidence that different types of chromatin are assembled at different times during S-phase remains indirect. A third genre of models suggests that replication timing is intimately linked to the three-dimensional (3D) organization of the genome [11, 12, 13, 14]. Recent findings have strengthened this association [15, 16•, 17], but the relationship of 3D chromosome organization to chromatin states and transcription remains as elusive as replication timing [18].
Here, we summarize recent progress toward understanding this complex liaison between copying and reading genetic information. We begin with some basic facts about replication control that necessitate framing any discussion of the significance of replication to gene expression in terms of large chromosomal domains. Next, developmental changes in replication timing are discussed, which involve large chromosome segments and accompany spatial repositioning and transcriptional changes for certain classes of promoters. We will then discuss recent experiments that address mechanisms by which chromatin influences replication time and vice versa. Finally, we will discuss how these multiple mechanisms might be related to 3D genome organization.
Section snippets
Replication timing is regulated at the level of large chromosomal domains
In order to discuss how replication timing might influence transcription, it is important to appreciate that replication is regulated at the level of large chromosomal domains. In mammals, rates of fork elongation are on average 1–2 kb/min and replication is bi-directional [19]. Hence, a single replicon (chromosomal DNA replicated from a single origin) will duplicate 100–200 kb within 1 h of a 10 h S-phase. Moreover, replication frequently proceeds via the nearly synchronous firing of several
Replication timing is regulated during development
If replication timing is related to transcription, then it should be subject to developmental control. The past several years witnessed first a challenge to and then a confirmation of the generality of replication timing changes during development. Until a few years ago, evidence other than during mammalian X-chromosome inactivation was restricted to a small number of genes whose replication time had been compared primarily between established, non-isogenic, transformed cell lines [9].
Developmental changes: unique isochores facing opposing forces?
The mouse genome-wide study showed that domains that changed replication timing were AT-rich and above a certain threshold of LINE-1 transposon density [8••], consistent with an earlier study [28]. Unexpectedly, it further revealed that these domains showed inverse correlation between GC content and gene density, which generally correlate with each other (Figure 1a). In general, isochore AT content is strongly associated with LINE-1 density, proximity to the nuclear periphery and late
Distinct classes of genes differ in their relationship to replication timing
While correlative, recent microarray studies have allowed us to sharpen hypotheses regarding the relationship between replication timing and transcription. It is now clear that the statistical relationship is similar across cell types and species and is confined to certain classes of genes. In both Drosophila and mouse, most genes replicate in the first third of S-phase and have an equally high probability of being expressed independent of their replication time within this period; a strong
Alterations in chromatin structure induce modest changes in replication timing
Several studies suggest that chromatin modifications directly regulate replication timing, but the effects of any particular modification are relatively minor and context dependent. Chemical inhibition of histone deacetylases (HDAC) can partially advance replication timing of several mammalian genes [42] as well as the Epstein–Barr Virus mini-chromosome [43•], while overexpression of a chromatin remodeling complex NoRC delays replication of rRNA genes [44]. In budding yeast, silent chromatin
Does replication timing affect chromatin structure?
Since chromatin is assembled at the replication fork, an appealing scenario is that replication timing dictates chromatin states that in turn regulate replication timing in the subsequent cell cycle, providing a means of epigenetic inheritance during somatic development (Figure 1 of [9]). Moreover, since replication is regulated at the level of replicons, a change in replication timing could rapidly transmit a change in chromatin state to many genes simultaneously. Clearly this attractive model
Large replication timing changes accompany radial subnuclear repositioning
In every case examined, dynamic developmental changes in replication timing accompany subnuclear repositioning [8••, 30]. Although a genome-wide survey of such relationship is currently impractical, spatial patterns of DNA replication in the nucleus change dramatically as cells move through S-phase, demonstrating a global coupling of subnuclear repositioning with replication-timing changes [19, 57] (Figure 1b). Moreover, replication timing is re-established during early G1-phase at the timing
Conclusions and future directions
Our understanding of replication timing remains a fragmented set of half-truths that are currently impossible to integrate into absolutes [64]. In fact, among the many experimental manipulations performed over the years, it is arguably only G1 nuclei before the TDP that display a globally disturbed replication-timing program [12, 13]. By contrast, the majority of chromatin manipulations have resulted in relatively minor effects. Moreover, modifications of chromatin proteins generally persist
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We would like to thank J Huberman, H Masukata, and M Schwaiger for helpful discussions, and P Norio for helpful comments. Research in the Gilbert lab is supported by NIH grant GM83337. ST is supported by the Nakayama Foundation for Human Science. We apologize to those who could not be cited owing to space limitation.
References (73)
Nuclear position leaves its mark on replication timing
J Cell Biol
(2001)- et al.
The spatial position and replication timing of chromosomal domains are both established in early G1-phase
Mol Cell
(1999) - et al.
The positioning and dynamics of origins of replication in the budding yeast nucleus
J Cell Biol
(2001) Replication in context: dynamic regulation of DNA replication patterns in metazoans
Nat Rev Genet
(2007)- et al.
A dynamic switch in the replication timing of key regulator genes in embryonic stem cells upon neural induction
Cell Cycle
(2004) - et al.
Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors
Cell
(2006) - et al.
Epstein-Barr virus episome stability is coupled to a delay in replication timing
J Virol
(2009) - et al.
The chromatin remodeling complex NoRC controls replication timing of rRNA genes
EMBO J
(2004) - et al.
Epigenomic replication: linking epigenetics to DNA replication
Bioessays
(2003) - et al.
Allele-specific nuclear positioning of the monoallelically expressed astrocyte marker GFAP
Genes Dev
(2008)
Genome-wide DNA replication profile for Drosophila melanogaster: a link between transcription and replication timing
Nat Genet
Coordination of replication and transcription along a Drosophila chromosome
Genes Dev
Replication timing of the human genome
Hum Mol Genet
DNA replication-timing analysis of human chromosome 22 at high resolution and different developmental states
Proc Natl Acad Sci U S A
Temporal profile of replication of human chromosomes
Proc Natl Acad Sci U S A
Pan-S replication patterns and chromosomal domains defined by genome-tiling arrays of ENCODE genomic areas
Genome Res
Global organization of replication time zones of the mouse genome
Genome Res
Global reorganization of replication domains during embryonic stem cell differentiation
PLoS Biol
Replication timing and transcriptional control: beyond cause and effect
Curr Opin Cell Biol
Shaping time: chromatin structure and the DNA replication programme
Trends Genet
The replication timing program of the Chinese hamster beta-globin locus is established coincident with its repositioning near peripheral heterochromatin in early G1 phase
J Cell Biol
The replication timing of CFTR and adjacent genes
Chromosome Res
Replication-timing-correlated spatial chromatin arrangements in cancer and in primate interphase nuclei
J Cell Sci
The radial arrangement of the human chromosome 7 in the lymphocyte cell nucleus is associated with chromosomal band gene density
Chromosoma
Nuclear organization of the genome and the potential for gene regulation
Nature
Heterogeneity of eukaryotic replicons, replicon clusters, and replication foci
Chromosoma
Replication dynamics of the yeast genome
Science
Progressive activation of DNA replication initiation in large domains of the immunoglobulin heavy chain locus during B cell development
Mol Cell
The temporal program of chromosome replication: genomewide replication in clb5{delta} Saccharomyces cerevisiae
Genetics
DNA replication timing: random thoughts about origin firing
Nat Cell Biol
Mapping sites where replication initiates in mammalian cells using DNA fibers
Exp Cell Res
Spatial distribution and specification of mammalian replication origins during G1 phase
J Cell Biol
Replication timing, chromosomal bands, and isochores
Proc Natl Acad Sci U S A
Differentiation-induced replication-timing changes are restricted to AT-rich/long interspersed nuclear element (LINE)-rich isochores
Proc Natl Acad Sci U S A
Neural induction promotes large-scale chromatin reorganisation of the Mash1 locus
J Cell Sci
Chromatin state marks cell-type and gender specific replication of the Drosophila genome
Genes Dev
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