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WIREs Syst Biol Med
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Role of the nuclear envelope in genome organization and gene expression

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Abstract Although often depicted as a static structure upon which proteinaceous factors bind to control gene expression, the genome is actually highly mobile and capable of exploring the complex domain architecture of the nucleus, which in turn controls genome maintenance and gene expression. Numerous genes relocate from the nuclear periphery to the nuclear interior upon activation and are hypothesized to interact with pre‐assembled sites of transcription. In contrast to the nuclear interior, the nuclear periphery is widely regarded as transcriptionally silent. This is reflected by the preferential association of heterochromatin with the nuclear envelope (NE). However, some activated genes are recruited to the nuclear periphery through interactions with nuclear pore complexes (NPCs), and NPC components are capable of preventing the spread of silent chromatin into adjacent regions of active chromatin, leading to the speculation that NPCs may facilitate the transition of chromatin between transcriptional states. Thus, the NE might better be considered as a discontinuous platform that promotes both gene activation and repression. As such, it is perhaps not surprising that many disease states are frequently associated with alterations in the NE. Here, we review the effects of the NE and its constituents on chromatin organization and gene expression. WIREs Syst Biol Med 2011 3 147–166 DOI: 10.1002/wsbm.101 This article is categorized under: Biological Mechanisms > Regulatory Biology

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Schematic of the nuclear pore complex (NPC). The NPC is a large proteinaceous structure that extends across the NE at points where the inner and outer nuclear membranes are fused, creating points of transit between the nucleoplasm and cytoplasm. Interactions with FG‐nups lining the central channel facilitate transport of import and export complexes through the NPC. Major sub‐complexes of the yeast NPC are shown in green (left side of image) and the corresponding mammalian homologs are shown in blue (right side of image). Positions of specific nucleoporins discussed throughout the text as having roles in gene expression are depicted. POM, pore outer membrane (integral NE proteins that anchor NPCs to the NE); nup, nucleoporin; NE, nuclear envelope; Mlp, myosin‐like protein; Tpr, translocated promoter region; FG‐nups, nucleoporins rich in phenylalanine‐glycine repeats.

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Chromosome tagging. The bacterial lac operator (LacO) and lac repressor (LacI) system in combination with green fluorescent protein (GFP) has been adapted for visualization of genome organization and dynamics in living cells.44 The system depends on high expression levels of LacI‐GFP, encoded either ectopically on a plasmid or genomically integrated, in conjunction with integration of a tandem array of 256 LacO sequences at the desired genomic locus. LacO sequences are tightly bound by LacI‐GFP and are visualized as a bright green focus by fluorescence microscopy (central foci in Zone 3; lower right panel). High expression levels of LacI‐GFP bound in relatively close proximity provide a focus that is easily observed with minimal excitation and can be repeatedly visualized with minimal photobleaching, making it ideal for time lapse microscopy in living cells. The addition of a fluorescent marker of the nuclear periphery such as a GFP‐tagged nucleoporin, Nup49‐GFP, and division of the nucleus into three concentric zones of equal area, zones 1–3, aid in determining gene positioning. Chromosome tagging has been successfully used to follow gene loci in both yeast and mammalian systems and has been adapted as a tool to tether genes to the nuclear envelope through the fusion of LacI to an integral inner nuclear membrane protein.29,40.

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