Nuclear organization: taking a position on gene expression

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Eukaryotic genomes are divided into chromosomes that occupy defined regions or territories within the nucleus. These chromosome territories (CTs) are arranged based on the transcriptional activity and chromatin landscape of domains. In general, transcriptionally silent domains reside at the nuclear periphery, whereas active domains locate within the interior. Changes in nuclear position are observed for stress-induced and developmentally regulated tissue-specific genes. Upon activation, these genes move away from a CT to inter-chromosomal space containing nuclear bodies enriched in gene expression machinery. Gene activation is not always accompanied by movement, as positioning is dictated by many determinants, including gene structure and the local genomic environment. Collectively, tissue-specific nuclear organization results from a culmination of inputs that result in proper transcriptional regulation.

Introduction

The nuclear envelope (NE) is a double membrane that defines the nucleus – the organelle in which processes such as DNA replication, transcription and mRNA processing take place. Advances in cytological methods and molecular genomics have provided insights on organization within the nucleus. Hybridization techniques that allow whole chromosomes to be ‘painted’ yield snap shot images of chromosomal arrangements, showing that chromosomes are largely confined to specific three-dimensional regions of the nucleus called chromosome territories (CTs, Figure 1a) [1••]. Gene-poor CTs and silenced genes are frequently found in association with the nuclear periphery, a similar location to that of heterochromatin (Figure 1a) [2]. By contrast, gene-rich CTs and active genes map to the nuclear interior. Sequence level organization has been obtained using chromosome conformation capture (3C) technology, which couples chemical cross-linking and massive parallel sequencing to define genome-wide relationships [3, 4, 5]. Results from these studies suggest that the genome is arranged as inter-digitated CTs rather than randomly inter-twined chromosomes [6]. Emerging from these investigations is a picture of the nucleus as an ordered organelle; the consequences of this organization are just being realized.

Section snippets

Nuclear organization during differentiation

Studies have linked nuclear organization to cellular differentiation. Cultured pluripotent mouse embryonic stem (ES) cells possess dispersed chromatin with limited compaction. Upon differentiation, they show changes in chromatin structure that include large-scale compaction of genomic domains [7]. Consistent with these findings, embryonic development proceeds from a single cell embryo possessing a ‘featureless’ nucleus with dispersed chromatin, to differentiated cells possessing nuclei with

The role of nuclear lamina in gene regulation

Peripheral localization of heterochromatin depends on proteins in the nuclear lamina, a network of proteins that line the inner side of the NE (Figure 1a and b) [10]. Genomic sites that contact the nuclear lamina have been mapped by DamID [11] and are called lamina-associated domains (LADs) [12]. LADs range in size from tens of kilobases to several megabases, are relatively gene poor, have low transcriptional activity and are enriched in repressive chromatin marks. LADs make up nearly 40% of

Effects of tethering to the NE

Parameters that define the transcriptional outcome resulting from NE association are unclear. To gain insights into these determinants, several groups developed systems that deliberately place genes near the nuclear periphery. In these studies, a two part system was used consisting of (1) multiple binding sites for the E. coli Lac I repressor protein positioned upstream of a reporter gene and (2) a transgene expressing a protein consisting of the Lac I DNA binding domain fused with either a

Effects of nuclear pore proteins on gene positioning

Multiple constituents of the NE contribute to genome organization. In addition to lamins, components of the nuclear pore complex (NPC) show chromatin association (Figure 1a). The interactions between nuclear pore proteins and chromatin are complex and not confined to the NE. In Drosophila, Nucleoporin Associated Regions (NARs), ranging in size from 5-kb to 500-kb, make up approximately 25% of the genome [19]. Many of the NARs localize to the nuclear interior and contain active genes that

Contribution of transcriptional machinery to nuclear organization

The interchromosomal space located between CTs contains a variety of nuclear substructures, referred to by many names including foci, speckles, bodies and spots (Figure 1a). The number and composition of these bodies depends on cell type [25]. Nuclear bodies are enriched in specific factors, such as those involved in transcription and RNA processing. While the function of these bodies has been challenging to discern, recent studies demonstrate an important role in nuclear organization.

Actively

Nuclear positioning and disease

The relative positioning of CTs can impact human disease. For example, chromosomal translocations that are commonly associated with human pathologies result from chromosome fusions [41]. These translocations arise from double-strand breaks that are repaired through non-homologous end joining between neighboring chromosomes. A consequence of translocation is the mis-positioning of many genes within the affected chromosomal region, which might contribute to the disease pathology. As CT

Conclusions and perspectives

The combination of cytology and new molecular genomic approaches to study protein–DNA interactions has revealed that the nucleus is an ordered, yet dynamic environment. Whole chromosomes are arranged in territories and inter-chromosomal spatial relationships are confined [46]; however, CTs and genes have the ability to change position. The mechanisms by which movement occurs within the nucleoplasm are largely unknown. Emerging evidence suggests that the myriad of nuclear bodies are likely to

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologize to authors of related studies that were not cited owing to space limitations. We would like to thank members of our laboratories for comments regarding the manuscript and NIH grants GM042539 and GM087341 to PKG, GM061513 and AR060012 to LLW, and Postdoctoral Fellowship GM085974 to MWV.

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