Review
Three-dimensional genome organization in interphase and its relation to genome function

https://doi.org/10.1016/j.semcdb.2007.08.007Get rights and content

Abstract

Higher order chromatin structure, i.e. the three-dimensional (3D) organization of the genome in the interphase nucleus, is an important component in the orchestration of gene expression in the mammalian genome. In this review we describe principles of higher order chromatin structure discussing three organizational parameters, i.e. chromatin folding, chromatin compaction and the nuclear position of the chromatin fibre. We argue that principles of 3D genome organization are probabilistic traits, reflected in a considerable cell-to-cell variation in 3D genome structure. It will be essential to understand how such higher order organizational aspects contribute to genome function to unveil global genome regulation.

Introduction

Cells of higher eukaryotes are able to efficiently and reliably orchestrate the transcriptional activity of their tens of thousands of protein-coding genes plus an unknown number of non-coding genes. To do so, the genome makes use of at least two ways of transcriptional regulation. First, a network of transcription factors acting in a combinatorial manner controls gene activation and repression. The second way to control gene expression in higher eukaryotes is via the spatial organization of the genome inside the interphase nucleus. While gene regulation controlled via the binding of transcription factors to promoter and enhancer sequences is extensively studied, little is known about how 3D genome organization contributes to transcriptional regulation.

Three levels of genome organization can be discriminated (Fig. 1). The first level is the one-dimensional (1D) arrangement of sequence elements such as regulatory and coding sequences or stretches of repetitive DNA in the genome. For instance on the linear DNA, genes coding for proteins with similar functions are sometimes clustered, e.g. genes coding for alpha and beta globin, Hox genes and core histones (for review see [1]). Also, co-localization and co-regulation of unrelated differentially expressed genes seems to be a common phenomenon [2], [3]. The human transcriptome map (HTM) depicts another type of 1D clustering: in the eukaryotic genome genes in general are not arranged randomly on the linear DNA strand but are clustered [4], [5]. The HTM shows that many highly expressed human genes occur in about 40 genomic domains, called regions of increased gene expression (ridges). Ridges are gene-rich, and contain highly expressed genes, among them many housekeeping genes [5], [6]. In addition, there are genomic areas that are gene-poor and contain mainly genes that, if expressed, have only a low transcriptional activity. Such clusters have been named anti-ridges. The second level of genome organization is defined by the interaction of DNA with proteins, the most prominent being the intimate interaction between DNA and histones to form nucleosomes. This interaction results in the formation of chromatin. Chromatin is the platform for many key processes in the eukaryotic interphase nucleus, such as transcription, replication and DNA repair. The epigenetic system defines different functional states of the chromatin fibre [7]. For instance, posttranslational histone modifications participate in the establishment of local chromatin structure that render a locus accessible or not for the transcriptional machinery.

The third and hierarchically highest level of genome organization is the spatial arrangement of the chromatin fibre in the three-dimensional (3D) space of the interphase nucleus. It has been shown that the eukaryotic nucleus is highly compartmentalised. For instance each chromosome occupies its own territory and has a preferred radial position in the eukaryotic nucleus [8]. Another example of compartmentalization is the spatial clustering of rRNA genes, which are present on different chromosomes, in the nucleolus [9]. It is likely that such compartmentalization of chromatin has a function in gene expression control.

In this review, we address several aspects of 3D genome organization in the mammalian interphase nucleus, focusing on large-scale chromatin structure, operationally defined as those aspects of chromatin structure that can be observed at the light microscopy level. Here, we will discriminate the following three parameters of 3D genome organization: (i) chromatin folding, (ii) chromatin compaction, and (iii) nuclear position of the chromatin fibre. We will highlight general aspects of large-scale chromatin structure and discuss the issue of chromosomal intermingling and the high degree of cell-to-cell variation in genome organization. Finally, we present an outlook of future directions of 3D genome research.

Section snippets

The folding path of the chromatin fibre in the interphase nucleus

An important parameter in 3D genome organization and nuclear compartmentalization is the higher order folding of the chromatin fibre, i.e. chromatin folding beyond the 30 nm fibre. To date, our understanding of how the chromatin fibre is spatially organized is remarkably limited for the simple reason that current imaging techniques do not allow one to directly follow the fibre and its folding path [10], [11]. Even by electron microscopy (EM), which is providing the highest microscopic

Compaction of chromatin

Chromatin compaction is another parameter of 3D genome organization that directly relates to chromatin folding and gene expression. Electron microscopy has shown that most chromatin of mammalian cells is present in relatively condensed irregularly shaped domains with a diameter in the range of a few tenths of a micrometer (for an overview see Fakan and Van Driel, this issue). Light microscopy studies support the idea that transcriptionally active chromatin domains are less condensed than

The nuclear position of the chromatin fibre

Another parameter that contributes to 3D genome organization is the spatial arrangement of the chromatin fibre in the interphase nucleus, i.e. its nuclear position. A correlation between transcriptional activity and position in the nucleus has been described for individual genes, for gene clusters and for complete chromosome territories. At the level of the individual gene, several groups have shown that active genes are positioned more towards the nuclear interior than inactive ones [30], [31]

Lack of intermingling supports the idea of a compact chromosomal fibre

As mentioned earlier, chromosomes are organized in discrete domains in the interphase nucleus named chromosome territories. Chromatin from neighbouring chromosome territories shows remarkably little intermingling [50]. Branco and Pombo [51] found that intermingling between different chromosome territories is only about 20% of the nuclear volume with the majority of overlap at the borders of the territories. A similar lack of considerable overlap has been shown for the p and q arms of

Cell-to-cell variation in higher order chromatin structure

In the above sections we summarized some principles of 3D chromatin organization with respect to chromatin fibre folding, compaction and nuclear position. However, measurements of these parameters, which all are related to genome function, revealed a considerable variation from cell to cell. For instance the radial position of gene-rich and gene-poor chromosome territories has been shown to differ considerably from cell to cell, while the average values display a significant dependency on gene

Effects of 3D genome structure on genome function

A large body of evidence shows that three-dimensional genome organization is related to genome function, in particular transcription. The idea that higher order chromatin structure is involved in gene regulation is supported by the occurrence of so-called chromatin diseases. The term ‘chromatin disease’ refers to human genetic disorders where either chromatin binding proteins or chromatin modifying enzymes are affected, resulting in impaired chromatin organization. Mutations in ‘chromatin

Conclusion and future directions

Given the high degree of genome structure and compartmentalization of the interphase nucleus one may predict that architectural components must exist that spatially organise the interphase nucleus. Up to now, however, no molecular systems that control functional chromosome organization have been identified. Amazingly, we do not even know of any mutation that causes major changes in nuclear and chromatin architecture, possibly due to protein redundancy or lethality. Nuclear matrix types of

Acknowledgements

We thank Rogier Versteeg (Academic Medical Centre, University of Amsterdam) for providing the transcriptome map of human chromosome 1 in Fig. 2. This work was supported by the European Commission as part of the 3DGENOME program: contract LSHG-CT-2003-503441.

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    1

    Present address: Institute of Molecular Biology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.

    2

    Present address: Institute of Human Genetics, Centre National de la Recherche Scientifique, Montpellier, France.

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