Nuclear pore complexes and regulation of gene expression
Introduction
In 1950, Callan and Tomlin used Xenopus laevis oocytes to perform the first electron microcopy studies of the nuclear envelope (NE) and observed that it was perforated by many large pores [1]. This was the first description of nuclear pore complexes (NPCs). Our understanding of NPCs has come a long way since that initial observation. Thanks to a momentous amount of work performed by many different groups over the last six decades we now know that NPCs are giant multiprotein channels of about 110 MDa in mammals that represent the sole gateway into the nucleus. At the structural level, NPCs have an eightfold rotational symmetry, and consist of a core ring embedded in the NE, two outer rings, one cytoplasmic and one nuclear, and eight filaments attached to these rings [2]. The nuclear filaments are also joined in a distal ring assembling a structure known as the nuclear basket. Despite being one of the largest protein complexes of eukaryotic cells these structures have a rather simple composition and are built by the repetition of roughly 30 different proteins known as nucleoporins [3, 4]. Recent studies combining structural information from the NPC itself and from individual nucleoporins has resulted in an unprecedented resolution of this structure [5•, 6•, 7].
In addition to their main function as mediators of nucleocytoplasmic molecule exchange, increasing evidence shows that NPCs regulate multiple cellular processes in a transport-independent manner [2]. Probably the most studied so far, and the focus of this review, is their role in genome organization and gene expression regulation.
Section snippets
Gene expression regulation by NPCs in yeast
The first evidence for a role of nuclear pore complexes in the regulation of gene expression came from studies in Saccharomyces cerevisiae. Though the initial observations of NPCs association with repressed telomeric and subtelomeric chromatin fueled the idea that the nuclear periphery was always associated with gene silencing, [8, 9], Menon et al. were the first ones to show that the Nup84 scaffold subcomplex of the NPC could act as transcriptional activator by itself [10]. Two other later
Gene expression regulation by NPCs in metazoans
Our knowledge of NPC-mediated regulation of gene expression in metazoans is considerably more limited than in yeast. The first connection of NPC components with chromatin modulation/gene expression regulation was described in Drosophila melanogaster with the identification of two nucleoporins, mTor/TPR and Nup153, as partners of the MSL dosage compensation complex [46]. This work showed that both nucleoporins were required for the localization of the MSL complex to the X chromosome and for the
Conclusions
Since the discovery of the first nucleoporin–gene interactions just 10 years ago, it has become clear that the NPC and its components play a pivotal role in the regulation of gene expression in multiple organisms. In this review, we have mostly focused in the positive regulation of gene expression by these proteins, but NPCs and nucleoporins have also been shown to associate and regulate silent/inactive chromatin [8, 26, 57••, 61, 62, 63, 64, 65]. Understanding how NPCs contribute to modulating
Acknowledgements
We apologize to all colleagues whose work could not be cited directly owing to space limitation. M.A.D. is a Pew Scholar in the Biomedical Sciences. Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number R01AR065083. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
References (65)
- et al.
Genome-wide localization of the nuclear transport machinery couples transcriptional status and nuclear organization
Cell
(2004) - et al.
Combining Spinach-tagged RNA and gene localization to image gene expression in live yeast
Nat Commun
(2015) - et al.
Developmentally induced changes in transcriptional program alter spatial organization across chromosomes
Genes Dev
(2005) - et al.
Nuclear pore association confers optimal expression levels for an inducible yeast gene
Nature
(2006) - et al.
Subnuclear positioning and interchromosomal clustering of the GAL1-10 locus are controlled by separable, interdependent mechanisms
Mol Biol Cell
(2016) - et al.
The mRNA export machinery requires the novel Sac3p–Thp1p complex to dock at the nucleoplasmic entrance of the nuclear pores
EMBO J
(2002) - et al.
The mRNA export factor Sus1 is involved in Spt/Ada/Gcn5 acetyltransferase-mediated H2B deubiquitinylation through its interaction with Ubp8 and Sgf11
Mol Biol Cell
(2006) - et al.
The nuclear pore-associated TREX-2 complex employs mediator to regulate gene expression
Cell
(2015) - et al.
Chromatin-bound nuclear pore components regulate gene expression in higher eukaryotes
Cell
(2010) - et al.
Nucleoporins directly stimulate expression of developmental and cell-cycle genes inside the nucleoplasm
Cell
(2010)
Nuclear pore proteins nup153 and megator define transcriptionally active regions in the Drosophila genome
PLoS Genet
Nucleoporin Nup98 associates with Trx/MLL and NSL histone-modifying complexes and regulates Hox gene expression
Cell Rep
A conserved role for human Nup98 in altering chromatin structure and promoting epigenetic transcriptional memory
PLoS Biol
The nucleoporin Nup153 regulates embryonic stem cell pluripotency through gene silencing
Genes Dev
Promoter- and RNA polymerase II-dependent hsp-16 gene association with nuclear pores in Caenorhabditis elegans
J Cell Biol
Chromatin boundaries in budding yeast: the nuclear pore connection
Cell
Experimental studies on amphibian oocyte nuclei. I. Investigation of the structure of the nuclear membrane by means of the electron microscope
Proc R Soc Lond B Biol Sci
Nuclear pore complex composition: a new regulator of tissue-specific and developmental functions
Nat Rev Mol Cell Biol
The yeast nuclear pore complex: composition, architecture, and transport mechanism
J Cell Biol
Proteomic analysis of the mammalian nuclear pore complex
J Cell Biol
Molecular architecture of the inner ring scaffold of the human nuclear pore complex
Science
Architecture of the symmetric core of the nuclear pore
Science
Toward the atomic structure of the nuclear pore complex: when top down meets bottom up
Nat Struct Mol Biol
Nuclear pore complexes in the organization of silent telomeric chromatin
Nature
Myosin-like proteins 1 and 2 are not required for silencing or telomere anchoring, but act in the Tel1 pathway of telomere length control
J Struct Biol
Reverse recruitment: the Nup84 nuclear pore subcomplex mediates Rap1/Gcr1/Gcr2 transcriptional activation
Proc Natl Acad Sci U S A
Nup-PI: the nucleopore–promoter interaction of genes in yeast
Mol Cell
Cotranscriptional recruitment to the mRNA export receptor Mex67p contributes to nuclear pore anchoring of activated genes
Mol Cell Biol
A negative feedback loop at the nuclear periphery regulates GAL gene expression
Mol Biol Cell
Gene loops function to maintain transcriptional memory through interaction with the nuclear pore complex
Genes Dev
H2A.Z-mediated localization of genes at the nuclear periphery confers epigenetic memory of previous transcriptional state
PLoS Biol
Cdk phosphorylation of a nucleoporin controls localization of active genes through the cell cycle
Mol Biol Cell
Cited by (89)
Nucleoporins facilitate ORC loading onto chromatin
2022, Cell Reports