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Dynamics and Interplay of Nuclear Architecture, Genome Organization, and Gene Expression Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Dynamics and interplay of nuclear architecture, genome organization, and gene expression Robert Schneider and Rudolf Grosschedl1 Max Planck Institute of Immunobiology, 79108 Freiburg, Germany The organization of the genome in the nucleus of a eu- The nucleus is organized in specific compartments karyotic cell is fairly complex and dynamic. Various fea- that include proteinaceous nuclear bodies, eukaryotic tures of the nuclear architecture, including compart- and heterochromatic chromatin domains, compartmen- mentalization of molecular machines and the spatial talized multiprotein complexes, and nuclear pores that arrangement of genomic sequences, help to carry out and allow for nucleocytoplasmic transport. The dynamic, regulate nuclear processes, such as DNA replication, temporal, and spatial organization of the eukaryotic cell DNA repair, gene transcription, RNA processing, and nucleus emerges as a central determinant of genome mRNA transport. Compartmentalized multiprotein function, and it is important to understand the relation- complexes undergo extensive modifications or exchange ship between nuclear architecture, genome organization, of protein subunits, allowing for an exquisite dynamics and gene expression. Recently, high-resolution tech- of structural components and functional processes of the niques have permitted new insights into the nuclear ar- nucleus. The architecture of the interphase nucleus is chitecture and its relationship to gene expression. linked to the spatial arrangement of genes and gene clus- In this review, we focus on the dynamic organization ters, the structure of chromatin, and the accessibility of of the genome into chromosome territories and chroma- regulatory DNA elements. In this review, we discuss re- tin domains. We also discuss the link of subnuclear cent studies that have provided exciting insight into the gene positioning with gene expression and how intra- interplay between nuclear architecture, genome organi- and interchromosomal interactions may contribute to zation, and gene expression. gene regulation. Within the nucleus many proteinaceous nuclear bod- ies, such as PML bodies or Cajal bodies, have been de- One of the striking features of the eukaryotic cell scribed (for detailed review, see Spector 2003). These nucleus, which carries and reads the genetic informa- bodies have a nonrandom positioning relative to spe- tion, is its functional and structural complexity. The hu- cific nuclear regions. Distinct functions have been at- man genome, containing some 35,000 genes and 3.2 bil- tributed to the various nuclear bodies, but we are just lion base pairs of DNA, is compacted 400,000-fold to fit beginning to understand the role of nuclear bodies in ∼ 3 within a nuclear volume of 1000 µm . The packing of gene transcription, RNA processing, and DNA repair. An DNA into chromatin is an extremely efficient way of interesting feature of nuclear bodies is the involvement storing the DNA within the nucleus. However, the ge- of post-transcriptional protein modifications, such as netic information has to become accessible for DNA- SUMOylation for PML bodies or arginine methylation dependent processes such as transcription, DNA repair, for Cajal bodies, in their generation and/or maintenance and replication. Most importantly, this accessibility is (for review, see Seeler and Dejean 2003; Heun 2007). regulated, as not all regions of the genome are active at a given time during the cell cycle. In recent years, increas- ing evidence has been accumulated suggesting that cis- Chromatin domains and trans-acting regulatory DNA sequences may not be the only determinants of gene expression, but that DNA In addition to the proteinaceous nuclear bodies, large- transactions also depend on the genomic position of scale chromatin domains exist that are mainly cytologi- genes, the subnuclear localization of DNA sequences, cally defined. In 1928, Heitz subdivided chromatin— and a complex interplay of the genome with specific fea- based on its microscopic appearance—into heterochro- tures of nuclear architecture. matin and euchromatin (Heitz 1928). Euchromatin was correlated with the bulk of transcribed chromatin, which [Keywords: Nuclear organization; chromatin; gene localization; chromo- is in an “open” chromatin conformation. In contrast, somal interactions] heterochromatin was correlated with more condensed 1Corresponding author. E-MAIL [email protected]; FAX 49-761-5108798. chromatin, which is enriched in inactive and silenced Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1604607. chromatin regions. Heterochromatin was considered to GENES & DEVELOPMENT 21:3027–3043 © 2007 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/07; www.genesdev.org 3027 Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Schneider and Grosschedl be transcriptionally inert. However, in the last few years maintained by flanking, ubiquitously expressed house- it has become clear that this correlation of chromatin keeping genes (Zhou et al. 2006), or by locus control structure and gene function is limited. Recently, the regions (Ragoczy et al. 2006). Bickmore group (Gilbert et al. 2004) analyzed chromatin According to the “transcription factory” model, RNA structure at a more global level. They fractionated chro- polymerase complexes, and transcription factors cluster matin into open, bulk, and closed chromatin fibers and and form a “cloud” of up to 20 DNA loops around the assayed the distribution of gene density and activity in transcription factory (Cook 1999; Faro-Trindade and these chromatin fractions. Surprisingly, they found a Cook 2006). The polymerase would be an immobile link between chromatin structure and gene density, in- component of the factory, and DNA loops would appear dependent of the status of gene activity. Open chromatin and disappear as polymerases initiate, elongate, and ter- fibers correlate with highest gene density, but not gene minate transcription. Each factory contains only one expression levels, whereas compact chromatin fibers type of RNA polymerase, and factories may be enriched generally have a low gene density, but can also contain in specific transcription factors involved in the transcrip- active genes (Gilbert et al. 2004). The ability of genes to tion of specific groups of genes (Bartlett et al. 2006). The be activated is not necessarily lost when chromatin is genes near the factory would be more likely to be tran- packed into more compact fibers. Conversely, inactive scribed. When released after termination, a gene would genes close to active genes in an open chromatin envi- still be near a factory and still carry the active histone ronment can stay inactive. In these cases, it is not the modifications that could keep it in an open state, leading location of a gene in heterochromatic or euchromatic to efficient reinitiation (Bartlett et al. 2006). In agree- chromatin domains that regulates gene activity, but ment with this concept, domains of decondensed and rather, other factors such as covalent modifications of recently transcribed chromatin carry histone marks that histones or DNA (Spector 2004). are associated with active transcription (Muller et al. 2007). What is the driving force to move the DNA template Transcription factories toward the transcription sites? One possibility is that Microscopic analysis of sites of active transcription in active polymerase can function as a motor that pulls in HeLa cell nuclei, using Br-UTP incorporation, revealed a its template. Optical tweezers experiments showed that nonhomogeneous clustering of ∼104 transcription sites, the force produced by a single polymerase molecule dur- with 8000 sites representing RNA polymerase II clusters ing transcription can be substantially larger than those and the rest RNA polymerase III transcription sites produced by the cytoskeletal motors kinesin and myosin (Pombo et al. 1999). The number of transcription sites (Yin et al. 1995). Alternatively, other molecular motors varies in different cells. These sites of active transcrip- such as nuclear actin and myosin could be involved in tion measure ∼80 nm in diameter, and they have been the relocalization of the DNA template. Another unre- termed “transcription factories” (Jackson et al. 1998). solved issue concerns the anchoring of transcription The textbook concept for a long time was that active sites. Many active genes and transcription factors are genes recruit the transcription machinery, and it is the associated with the “nuclear matrix,” an ill-defined and transcription machinery that relocates to the active genes. controversial nuclear substructure (Jackson and Cook However, three-dimensional fluorescence in situ hybrid- 1985; Davie 1995; Iborra et al. 1996; Kumar et al. ization (3D-FISH), immunofluorescence, and chromo- 2007). some conformation capture (3C) analysis, which detects Although the model of “transcription factories” fits close physical proximity between remote chromatin seg- with the observation that active genes can transiently ments (Dekker 2006), provided new insights into the or- cluster (Simonis et al. 2006), one has to keep in mind ganization of transcription sites and raised questions that biochemical evidence for these “transcription fac- about this dogma. Using a combination of these meth- tories,” including their isolation and functional
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