Replication timing and transcriptional control: beyond cause and effect—part II

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Replication timing is frequently discussed superficially in terms of its relationship to transcriptional activity via chromatin structure. However, so little is known about what regulates where and when replication initiates that it has been impossible to identify mechanistic and causal relationships. Moreover, much of our knowledge base has been anecdotal, derived from analyses of a few genes in unrelated cell lines. Recent studies have revisited long-standing hypotheses using genome-wide approaches. In particular, the foundation of this field was recently shored up with incontrovertible evidence that cellular differentiation is accompanied by coordinated changes in replication timing and transcription. These changes accompany subnuclear repositioning, and take place at the level of megabase-sized domains that transcend localized changes in chromatin structure or transcription. Inferring from these results, we propose that there exists a key transition during the middle of S-phase and that changes in replication timing traversing this period are associated with subnuclear repositioning and changes in the activity of certain classes of promoters.

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.

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