From hypothesis to mechanism: uncovering nuclear pore complex links to gene expression

Abstract

The gene gating hypothesis put forth by Blobel in 1985 was an alluring proposal outlining functions for the nuclear pore complex (NPC) in transcription and nuclear architecture. Over the past several decades, collective studies have unveiled a full catalog of nucleoporins (Nups) that comprise the NPC, structural arrangements of Nups in the nuclear pore, and mechanisms of nucleocytoplasmic transport. With this foundation, investigations of the gene gating hypothesis have now become possible. Studies of several model organisms provide credence for Nup functions in transcription, mRNA export, and genome organization. Surprisingly, Nups are not only involved in transcriptional events that occur at the nuclear periphery, but there are also novel roles for dynamic Nups within the nucleoplasmic compartment. Several tenants of the original gene gating hypothesis have yet to be addressed. Knowledge of whether the NPC impacts the organization of the genome to control subsets of genes is limited, and the cooperating molecular machinery or specific genomic anchoring sequences are not fully resolved. This minireview summarizes the current evidence for gene gating in Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and mammalian model systems. These examples highlight new and unpredicted mechanisms for Nup impacts on transcription and questions that are left to be explored.

FIG 1

Shared and distinct roles for Nups in gene gating across different model systems. (A) In S. cerevisiae, Nups are required to recruit multiple genes to the nuclear periphery for optimal gene expression. This mechanism requires specific DNA sequences in the promoters termed DNA zip codes. (B) The developmentally induced myo-3 and pha-4 promoters in C. elegans are positioned in the nucleoplasmic interior when transcriptionally active, whereas the heat shock-induced promoter hsp-16.2 is juxtaposed to the NPC, implying distinct gene gating mechanisms for different contexts of gene expression. (C) Drosophila Nups, including Nup98, Sec13, Nup50, and Nup62, impact transcriptional events in nucleoplasm and at the NPC. NARs are defined regions of the genome that interact with the Nup153 and Megator Nups. (D) The dynamic Nup98 regulates transcriptional memory of gamma interferon (IFN-γ)-induced genes in human cells. In mice, cell type-specific expression of the NE-anchored Nup210 regulates gene expression during myogenesis. Channeled diffusion of mRNPs from the nuclear interior to NPCs occurs through interchromatin compartments. Active genes (green circles), inactive genes (red circles), euchromatin and interchromatin compartments (light pink), and heterochromatin (dark pink) are indicated. The figure is not drawn to scale.