The role of nuclear pores in gene regulation, development and disease

Abstract

Nuclear-pore complexes (NPCs) are large protein channels that span the nuclear envelope (NE), which is a double membrane that encloses the nuclear genome of eukaryotes. Each of the typically 2,000-4,000 pores in the NE of vertebrate cells is composed of multiple copies of 30 different proteins known as nucleoporins. The evolutionarily conserved NPC proteins have the well-characterized function of mediating the transport of molecules between the nucleoplasm and the cytoplasm. Mutations in nucleoporins are often linked to specific developmental defects and disease, and the resulting phenotypes are usually interpreted as the consequences of perturbed nuclear transport activity. However, recent evidence suggests that NPCs have additional functions in chromatin organization and gene regulation, some of which might be independent of nuclear transport. Here, we review the transport-dependent and transport-independent roles of NPCs in the regulation of nuclear function and gene expression.

Figure 1

Nuclear pores and chromatin organization. (A) Schematic illustration of the NPC. The three different classes of Nups and their relative locations within the NPC are shown. (B) Electron micrograph image of a mammalian nucleus, illustrating the positioning of the NE against darkly stained condensed heterochromatin, and of the nuclear pores (arrowheads) against the lighter stained open euchromatin. Reproduced with permission from http://synapses.clm.utexas.edu (J. Spacek). Gp210, glycoprotein of 210 kDa; hCG1, candidate gene 1; INM, inner nuclear membrane; Ndc1, nuclear division cycle 1; NE, nuclear envelope; NPC, nuclear-pore complex; Nup, nucleoporin; ONM, outer nuclear membrane; Pom121, pore membrane protein of 121 kDa; Rae1, RNA export 1; Sec13, secretory mutant 13; Seh1, Sec13 homologue; Tpr, translocated promoter region.

Figure 2

Models of transport-dependent and transport-independent mechanisms of gene regulation by the nuclear-pore complex. The NPC consists of stable core components (dark blue) and peripheral Nups (red), which are often dynamic. (A) Transport-dependent regulation might involve interactions between cell type-specific TFs (green) and a specific NPC component, between an IMP (gray) that carries a TF (orange) and a specific FG Nup, or between a given mRNA and a particular Nup. (B) Transport-independent regulation might involve chromatin tethering to the NPC (nucleosomes are shown as gray discs), or the recruitment of active genes (Pol II is shown in green) to the NPC through interactions with SAGA/Sus1 (gray), mRNA or the associated mRNA export and processing machinery (light blue). Alternatively, dynamic Nups (red) could shuttle away from the nuclear pore and interact with active genes, mRNA or mRNA export/processing machinery inside the nucleus. IMP, import receptor; mRNA, messenger RNA; NPC, nuclear-pore complex; Nup, nucleoporin; Pol II, RNA polymerase II; SAGA, Spt-Ada-Gcn5-Acetyltransferase; Sus1, suc synthase 1; TF, transcription factor.

Maya Capelson

Martin W. Hetzer