Genome Organisation and Chromosome Architecture from Interphase to Metaphase

Abstract

It is well established that vertebrate and other eukaryotic genomes are compositionally compartmentalised into long (≥200 Kb) sequences, the isochores, that are fairly homogeneous in their basic composition, and belong to a small number of families (five in the human genome). On the other hand, recent investigations in many laboratories have led to a new vision of interphase chromatin, which basically consists of large loops (average size ∼186 Kb in the case of the human genome) and anchors held together by ‘architectural’ proteins such as CTCF (the CCCTC‐binding factor) and cohesin. A very recent analysis has revealed correlations between isochores from different families and the architectural features of chromosomes through the cell cycle. This leads to a unifying view of the genome organisation and chromosome architecture.

Key Concepts

  • The long‐range compositional organisation of the genome of vertebrates and of other eukaryotes (i.e. the isochore organisation) is correlated with the chromosome architecture through the cell cycle. This leads to a unifying view of genome organisation and chromosome architecture.
  • In spite of very extensive investigations over many years, the organization of the eukaryotic genome and the architecture of chromosomes from interphase to metaphase are two problems that are still open because of their complexity.
  • A combination of a large‐scale compositional analysis of vertebrate genomes and of the recent results on the architecture of interphase chromatin led to a solution of those problems.
  • The large‐scale compositional analysis revealed that vertebrate genomes consist of long (≥200 kilobases) fairly homogenous DNA segments, the isochores. Cross‐linking of contact regions of chromatin and sequencing (chromosome conformation captureand its variants) provided a picture of three‐dimensional interphase chromatin structure.
  • The long‐range compositional organization of the genome of vertebrates and of other eukaryotes (i.e., the isochore organization) was shown to be correlated with the chromosome architecture through the cell cycle.
  • The correlations between the isochore organization of the genome and the chromosome architecture through the cell cycle (especially the architecture of interphase chromatin structure) led to a unifying view of genome organization and chromosome architecture.

Keywords: cell cycle; chromosome architecture; genome organisation; interphase; metaphase; nuclear structure

Figure 1. (a) Compositional profile of human chromosome 21 as seen through non‐overlapping 100‐Kb windows. DNA stretches from isochore families L1, L2, H1, H2 and H3 are represented here in different colours, deep blue, light blue, yellow, orange, red, respectively. The ordinate values are the minima GC values (valleys) between isochore families (see (b)). The red horizontal line at 41% GC separates the two (GC‐poor and GC‐rich) genome compartments. (b) . The histogram displays the isochores from the human genome as pooled in bins of 1% GC. The Gaussian profile shows the distribution of isochore families that are represented in different colors as in (a). Gene densities (and all other structural and functional properties tested; see Table) of the isochore families define a genome desert and a genome core (separated by a vertical broken red line). Reproduced from Bernardi, 2015 © Creative Commons Attribution (CC BY) license.
Figure 2. (a) (a topologically associating domain, TAD, with three sub‐domains in this figure). The DNA framework of the loops are large GC‐poor isochores. The loop is closed by anchors (chromatin boundaries) made by GC‐rich isochores that interact with two architectural proteins, CTCF (boxes) and cohesin (green oval). A number of sub‐domains have their loops anchored by CTCF and cohesin sub‐units (boxes) (see Text). (b) of the domains and sub‐domains in a linear chromatin structure, possibly in a ‘beads‐on‐a string’, 10‐nm conformation. Architectural proteins such as CTCF are visualised as still linked to their binding sites (see Text). (c, d) into 30‐nm fiber loops anchored by the architectural proteins and compaction into three early prophase, single‐isochore bands R‐G‐R, the central one being a multiple‐loop band, the flanking ones single‐loop bands. (e) into multiple‐isochore bands. In the example shown, the R‐G‐R single‐isochore bands coalesce into an R band because of a ‘majority rule’ (2 R vs 1 G). Architectural proteins form a discontinuous protein scaffold of the chromosome (see Text). Reproduced from Bernardi, 2015 © Creative Commons Attribution (CC BY) license.
Figure 3. The banding pattern of chromosome 21: (a) at early prophase, (b) at prometaphase and (c) at metaphase. Vertical lines connect isochore blocks or single isochores (indicated by asterisks), of early prophase bands with prometaphase bands. The following coalescence process (B→C) leads to different ratios of prometaphase to metaphase bands, 1:1, 3:1, 5:1. Reproduced from Bernardi, 2015 © Creative Commons Attribution (CC BY) license.
Figure 4. Scheme of the coalescence of prometaphase into metaphase bands (from Bernardi, ). The scheme of the loops at the bottom is from Naumova (). Reproduced with permission from Naumova et al. (2013) © The American Association for the Advancement of Science.
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Further Reading

Bernardi G (2004) Structural and Evolutionary Genomics. Natural Selection in genome Evolution. Amsterdam: Elsevier (reprinted in 2005). This out‐of‐print book is freely available at www.giorgiobernardi.eu.

Bernardi G (2007) The neoselectionist theory of genome evolution. Proceedings of the National Academy of Sciences of the United States of America 104: 8385–8390.

Bernardi G (2015) Chromosome architecture and genome organization. PLoS One 10: e0143739.

Cremer T and Cremer M (2010) Chromosomal territories. Cold Spring Harbor Perspectives in Biology 2: a003889.

Dixon JR, Selvaraj S, Yue F, et al. (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 85: 376–380.

Naumova N, Imakaev M, Fudenberg G, et al. (2013) Organization of the mitotic chromosome. Science 342: 948–953.

Nora EP, Lajoie BR, Schulz EG, et al. (2012) Spatial partitioning of the regulatory landscape of the X‐inactivation centre. Nature 485: 381–385.

Rao SSP, Huntley MH, Durand NC, et al. (2014) A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159: 1665–1680.

Sexton T and Cavalli G (2015) The role of chromosome domains in shaping the functional genome. Cell 160: 1049–1059.

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Bernardi, Giorgio(May 2016) Genome Organisation and Chromosome Architecture from Interphase to Metaphase. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005123.pub3]