Genome Regulation

How do chromosome territory dynamics affect gene redistribution?

The spatial organization of chromatin within the 3-dimensional space of a chromosome territory enables the co-localization of co-transcribed genes and their transcriptional foci. Many gene positioning studies have shown that individual genes often loop out of their chromosomal territory to co-localize with transcription factories. This often leads to interchromosomal compartments becoming enriched with intermingling chromatin loops, either from the same chromosome, or different chromosomes. It has been suggested that this repositioning can occur upon transcriptional activation [1][2][3].

Measuring the diffusional motion of chromatin by sub-micrometer single-particle tracking, a characteristic confinement radius (significantly smaller than the size of the nucleus) can be determined for each locus. This demonstrates that, at least in yeast, centromers and telomers have a radii of confinement approximately twice as small as the rest of the chromosomal sites [4]. The authors also showed that in yeasts and drosophila, chromatin constantly undergoes diffusive Brownian motion, constrained by confinement regions of gene loci, which rarely exceed 0.3 µm [4].

Importantly, the repositioning of genes through chromosome territory dynamics is not always random, and the spatial redistribution of genes may involve specific nuclear structures or landmarks. This may have a significant effect on gene expression [5]. Local compaction dynamics, long-distance interactions with alternative sections of DNA, and interactions with nuclear scaffolds [6] all play a role in the control of gene redistribution. Where interactions between DNA and nuclear scaffolds occur, anchor points , known as matrix attachment regions (MARs), are formed.

Long-distance chromatin interactions may either involve the establishment of physical contacts between two sequence elements that are not adjacent to each other, but are present on the same linear chromosome (as is the case when enhancers interact with promoters), or between loci on different chromosomes [6][7]. Importantly, with most interactions between loci occurring in only a small fraction of cells at any given time, long-range contacts are considered to be, at least in part, random, and are therefore difficult to predict [8]. Despite these difficulties, it has been suggested that the nucleoskeleton is involved in the regulation of long-distance contacts. For example, Chuang et al. [9] observed a fast (0.1-0.9 µm/min) long-range (1-5 µm) directional movement of transgenic chromatin arrays. Nuclear actin together with myosin – two important components of the nucleoskeleton – were proposed to serve as molecular motors that direct the movement of chromatin towards a given target region [10]. This was supported when the movement of actin arrays was blocked by the expression of mutant nuclear myosin I or mutant actin. Moreover, with the actin mutant unable to polymerize, the looping of U2 snRNA genes towards coiled bodies was also abolished [11].

Interactions between genes and nuclear landmarks also affect gene transcription. These landmarks, which are distinct nuclear regions, include the nuclear lamina (NL), nuclear pore complexes (NPCs) and the nucleolus (reviewed in [12][13][14]).

The nuclear periphery is often found to preferentially interact with transcriptionally silent chromatin, which is characterized by a low gene density. It has been proposed that the nuclear periphery itself creates a specific environment that favors histone deacetylation and gene silencing [15]. Indeed, in yeast cells (which generally lack nuclear lamin), gene silencing resulted from the tethering of a gene locus to the periphery [15]. This suggests that in mammals, the nuclear periphery is heterogeneous, with microdomains of different compositions having different effects on genome function [12]. Takizawa et al. [5] proposed that simply being near the periphery without physically associating with the NL is not enough to induce gene repression.

Nuclear pore complexes represent another distinct microenvironment; however, in contrast to the nuclear periphery this landmark is often associated with gene activation [16][17]. In yeast cells, the highly transcribed ribosomal protein (RP) is connected with NPCs via the actin-related protein, Arp6 [18]. Interestingly, interactions between chromatin and NPCs may take place both in and away from the nuclear periphery, making the dynamic movement of lamins and nuclear pore proteins integral to gene regulation [19]. The exact dynamics that drive these interactions in the nucleoplasm remains poorly understood.

The nucleolus may also anchor specific chromatin loci. In addition to rRNA genes, it often harbors large genomic regions (median size 750 kb) that are enriched in centromeric satellite repeats and inactive gene clusters. Centromeric regions are also found associated with nuclear lamina, suggesting that centromeres are distributed between the nuclear lamina and nucleoli [14].

The main function of nucleolus is the synthesis of ribosomal RNA and assembly of ribosomal particles. Nucleoli are often enriched with centromeric satellite repeats and inactive gene clusters.

Despite the current evidence highlighting the influence of chromosome territory dynamics in the regulation of gene expression, little is known on the mechanisms behind these processes. For example, it is unclear how and why activated genes are translocated, or loop, from one chromosome territory to another. One plausible scenario involves the transduction of mechanical stimuli to the nucleus directly via the cytoskeleton. In such cases, cytoskeletal forces induce nuclear deformation (i.e., elongation or squeeze) and subsequently, alter chromosome topology and gene expression [20]. The nucleoskeleton (i.e., nuclear actin and myosin) provides another mechanism to control the long-distance directional movement of genes [10], but this is likely to be restricted to specific genes, e.g. U2 snRNA [11]. Currently, the extent to which genes move through active guidance as opposed to diffusion, remains unclear.

References

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