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. 2022 Jan;14(1):a039438. doi: 10.1101/cshperspect.a039438

The Nuclear Pore Complex as a Transcription Regulator

Michael Chas Sumner 1, Jason Brickner 1
PMCID: PMC8725628  PMID: 34127448

Abstract

The nuclear pore complex (NPC) is a highly conserved channel in the nuclear envelope that mediates mRNA export to the cytosol and bidirectional protein transport. Many chromosomal loci physically interact with nuclear pore proteins (Nups), and interactions with Nups can promote transcriptional repression, transcriptional activation, and transcriptional poising. Interaction with the NPC also affects the spatial arrangement of genes, interchromosomal clustering, and folding of topologically associated domains. Thus, the NPC is a spatial organizer of the genome and regulator of genome function.

Eukaryotic cells spatially organize their genomes in a nonrandom fashion that both reflects and facilitates transcription regulation (Misteli 2020). Electron micrographs of metazoan nuclei show that heterochromatin associates with the nuclear lamina at the nuclear periphery in many cell types (Fig. 1; Jost et al. 2012). While it is true that heterochromatin is primarily positioned near the nuclear lamina or chromocenters, this can vary with cell type and organism (Zykova et al. 2018; Falk et al. 2019). While some organisms lack lamins, all eukaryotic nuclei are punctuated by hundreds to thousands of nuclear pore complexes (NPCs) that facilitate exchange between the nucleoplasm and cytoplasm. These structures also physically interact with specific sites in the genome, impacting their positioning and their expression.

Figure 1.

Figure 1.

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Spatial organization of nuclear pore complex (NPC) component interactions with chromatin. (A) (Right) Portion of metazoan nucleus where green represents euchromatin and red denotes heterochromatin. (Left) Peripheral chromatin adjacent to the nuclear lamina (red) and the NPC (green). (B) (Right) Portion of a Saccharomyces cerevisiae nucleus. Color indicates the space where NPC–chromatin interactions can occur (telomere silencing interactions in red, euchromatin transcription initiation in green). (Left) Insets show that the effects on transcription only occur at the nucleoplasmic face of the nuclear pore.

NPCs act as a gate between the cell's two major compartments: the cytoplasm and the nucleus. Ubiquitous and essential, pores facilitating the transfer of material across the nuclear envelope were discovered at a time when there was still an ongoing debate about the existence of an organized nuclear membrane (Callan and Tomlin 1950; Watson 1955). Work over the intervening decades has revealed NPC function, organization, mechanism, and structure (Gall 1967; Goldberg and Allen 1992; von Appen and Beck 2016). Approximately 30 unique proteins make up the core eightfold radially symmetrical channel, with subcomplexes that extend from its cytoplasmic and nucleoplasmic faces, comprising additional proteins. NPC subunits with access to the nucleoplasm physically interact with chromatin and can impact their transcriptional regulation.

Based on electron micrographs showing that chromatin near NPCs was less condensed than adjacent, lamin-associated heterochromatin, Günter Blobel hypothesized that positioning of active genes near NPCs would enhance mRNA export (Blobel 1985). Years later, work from several systems confirmed that the NPC physically associates with active genes, impacting the spatial organization of genes and gene expression (Brickner and Walter 2004; Casolari et al. 2004; Guglielmi et al. 2020). To date, a convincing role for this interaction in promoting efficient mRNA export has not been established. However, data from yeast, flies, and mammals suggests that nuclear pore protein (Nup) interaction can alter gene expression to improve viability during stress conditions, maintain epigenetic memory of previous expression states, and promote tissue differentiation (Brickner and Walter 2004; Brickner et al. 2007; Liang et al. 2013a).

Here we review multiple, evolutionarily conserved ways the NPC regulates transcription. Widening our collective understanding of how the NPC regulates gene expression will help guide future research in epigenetics and transcriptional mechanisms.

MOLECULAR MECHANISM OF INTERACTION WITH THE NPC

Repositioning and interaction of active genes with the yeast NPC requires both nucleoplasmic nuclear pore proteins such as Nup1, Nup2, Nup60, Mlp1, and Mlp2 (Cabal et al. 2006; Luthra et al. 2007; Ahmed et al. 2010; Light et al. 2010). Furthermore, interaction with the NPC requires binding of sequence-specific DNA-binding transcription factors (TFs) to cis-acting DNA sequences near promoters (Schmid et al. 2006; Ahmed et al. 2010; Randise-Hinchliff et al. 2016). The binding sites of such transcription factors function as DNA zip codes; they are both necessary and sufficient to mediate repositioning to the periphery and interaction with Nups (Ahmed et al. 2010; Brickner et al. 2012). Of course, the NPC interacts with many complexes involved in transcription initiation, elongation, and RNA maturation. TFs, Nups, and complexes involved in mRNA export (i.e., TREX2 and Mex67) and transcription (Mediator, SAGA histone acetyltransferase) are required for targeting the nuclear periphery (Dieppois et al. 2006; Ahmed et al. 2010; Jani et al. 2014). However, several experiments argue that TFs and Nups play a direct role, while the others do not. Conditional inactivation of TFs and Nups, but not TREX-2, Mex67, Mediator, or SAGA, leads to rapid loss of peripheral localization (Brickner et al. 2019). Furthermore, tethering a TF at an ectopic site leads to peripheral localization and physical interaction with Nups but does not lead to chromatin binding with Mediator, TREX-2, or Mex67. Finally, for Gcn4-targeted genes, TF overexpression bypassed the requirement for SAGA and Mediator component null mutants for targeting chromatin to the nuclear periphery but still required Nup2 (Brickner et al. 2019). These results suggest that TFs and Nups play a direct role in targeting genes to the nuclear periphery.

This is a common function of TFs: when tethered to a chromosomal locus, most yeast TFs can induce Nup-dependent peripheral localization (Brickner et al. 2019). Importantly, these TFs include activators, repressors, and chromatin factors, suggesting that the interaction with the NPC may impinge upon transcription and chromatin structure in more than one way.

THE NPC AND GENE SILENCING

The chromosomal position of a gene can impact its expression; genes near centromeres or telomeres show reduced recombination and transcription, a phenomenon known as “position effect” (Weiler and Wakimoto 1995). Position effects often reflect the spreading of silencing factors from sites of recruitment (Gottschling et al. 1990). For example, in budding yeast, telomeres and adjacent sequences are transcriptionally silenced by the recruitment of Rap1, and the silencing factors Sir2, Sir3, and Sir4 (Fig. 2A; Gotta et al. 1996). Rap1 is a sequence-specific DNA-binding protein that binds to telomeres and recruits Sir2, Sir3, and Sir4. The Sir proteins deacetylate histones and spread down the chromosome arms into subtelomeric regions, establishing and maintaining silenced chromatin. Telomeres localize at the nuclear periphery, and nuclear envelope membrane proteins such as Esc1 and Mps4, as well as Nups like those that make up the inner and outer ring subcomplexes (i.e., Nup170, Nup145, and Nup60) as well as nucleoplasmic TPR homologs (Mlp1 and Mlp2; Galy et al. 2000), act as a physical anchor to recruit and stabilize the Rap1/Sir3/Sir4 complex with chromatin and maintain telomere positioning at the nuclear periphery (Van de Vosse et al. 2013; Lapetina et al. 2017). Loss of these nuclear pore proteins leads to a defect in the silencing of telomeres and the silent mating-type loci (Feuerbach et al. 2002). In this way, the nuclear envelope and Nups contribute to both the spatial organization and transcriptional silencing of yeast telomeres.

Figure 2.

Figure 2.

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Nuclear pore complex (NPC) proteins affect transcription. (A–C) Schematic of metazoan nucleus (left) or yeast nucleus (right). (A) Nup-mediated transcriptional repression. (Left) Soluble Nup153 interacts with CTCF at topologically associated domain (TAD) boundaries in Homo sapiens. Heterochromatin at the nuclear periphery interacts with Nup93 and maintains Polycomb repressive complex (PRC) histone modification in Drosophila melanogaster. (Right) Telomere recruitment to the Saccharomyces cerevisiae NPC facilitates binding of chromatin silencing Sir factors. (B) Nup-mediated transcriptional activation. (Left) Chromatin decompaction by recruitment of Nups and transcriptional activation by recruitment of Nup98. (Right) Transcription factor (TF)- and Nup-dependent stimulation of transcription in S. cerevisiae. (C) Nup-dependent transcriptional poising. (Left) Nup98 recruitment can both enhance promoter–enhancer looping and, potentially, through recruitment of specific histone methyltransferases. (Right) Schematic of a Nu100-dependent chromatin changes leading to transcriptional poising during memory in S. cerevisiae. (MRS) Memory recruitment sequence.

In metazoan cells, genes interact with both NPC-associated Nups at the nuclear periphery and soluble Nups localized throughout the nucleoplasm (Griffis et al. 2002; Capelson et al. 2010; Kalverda et al. 2010; Liang et al. 2013b). At the fly NPC, active and silent genes interact with distinct Nups (Nup107 and Nup93, respectively; Gozalo et al. 2020). Polycomb repressive complexes (PRCs) catalyze methylation of H3K27 to establish and maintain facultative heterochromatin (Fig. 2A). More than a third of Polycomb-associated domains also physically interact with Nup93. Compared to other Polycomb domains, those that interacted with Nup93 had increased PRC presence and were more likely to be positioned at the nuclear periphery (Gozalo et al. 2020). Finally, Nup93 contributes to transcriptional silencing of these regions. Thus, interaction of Nups can also promote transcriptional silencing and heterochromatin formation in animals.

Interaction of Nups with the genome can also impact chromosome folding. Boundary elements and the chromatin architectural proteins that localize to them (CTCF and cohesin) interact with Nup153 to stabilize their organization in physical space and enhance insulation between TADs (Fig. 2B; Kadota et al. 2020). Knockdown of Nup153 leads to improper TAD formation and ectopic enhancer function across boundary domains. Embryonic stem cells are insensitive or slow to respond to epidermal growth factor following Nup153 knockdown. Likewise, looping of promoters with certain enhancers is stimulated by Nup98 in Drosophila (Pascual-Garcia et al. 2017). Finally, Nups are implicated in the formation of senescence-associated heterochromatin foci (SAHF) during oncogene-induced senescence (Boumendil et al. 2019). During this process, the heterochromatin reorganizes from the periphery to coalesce in the nucleoplasm, followed by cell cycle arrest and secretion of inflammatory cytokines. Knockdown of TPR blocks SAHF formation and reorganization of heterochromatin and cytokine secretion, suggesting that TPR influences the position and expression of heterochromatin.

The NPC and Transcriptional Activation

The NPC can also positively affect transcription. In budding yeast, genome-wide chromatin immunoprecipitation studies showed that hundreds of transcriptionally active loci interact with Nups (Casolari et al. 2004, 2005) and inducible genes reposition from the nucleoplasm to the nuclear periphery upon activation (Brickner and Walter 2004; Casolari et al. 2004). Likewise, in flies and mammals, thousands of chromosomal sites, including many euchromatic, transcriptionally active regions, interact with nuclear pore proteins (Brown et al. 2008; Capelson et al. 2010; Kalverda et al. 2010; Liang et al. 2013a; Jacinto et al. 2015; Pascual-Garcia et al. 2017). These interactions enhance transcription and increase the rate of expression; disrupting the interaction with nuclear pore proteins reduces the rate and extent of transcriptional induction of many genes in budding yeast and animals (Brickner et al. 2007, 2012, 2019; Ahmed et al. 2010; Capelson et al. 2010; Light et al. 2010, 2013; Liang et al. 2013a; Jacinto et al. 2015; Pascual-Garcia et al. 2017). Moving a DNA zip code from upstream of the promoter to downstream of the coding sequence had an interesting effect. Such a locus was targeted to the periphery but was still defective for transcription (Ahmed et al. 2010), suggesting that the physical interaction with the promoter is critical for promoting transcription. However, tethering of inducible genes to the nuclear envelope or the NPC is not sufficient to cause transcriptional activation (Brickner and Walter 2004; Green et al. 2012; Texari et al. 2013).

How do Nups promote transcription? Single molecule RNA FISH experiments suggest that disrupting the interaction with the yeast NPC reduces the fraction of cells expressing the GAL1 gene (Brickner et al. 2016). For the subset of cells that express GAL1, the level of expression is normal. Because transcription occurs through stochastic bursts, mRNA output is the product of burst frequency, burst duration, and burst amplitude (Rodriguez and Larson 2020). This observation suggests that interaction with Nup2 quantitatively increases transcription by increasing the burst frequency or burst duration, without affecting burst amplitude. Because enhancers have been implicated in burst frequency, while core promoter strength has been implicated in burst amplitude (Tunnacliffe et al. 2018; Larsson et al. 2019), this suggests that Nups stimulate enhancer function.

An additional hint into the role of yeast Nups in transcriptional activation comes from structure–function analysis of the Gcn4 TF. Gcn4 is essential for both transcriptional activation and NPC interaction of many target genes (Hope and Struhl 1985; Rawal et al. 2018; Brickner et al. 2019). Tethering Gcn4 to a nucleoplasmic locus is sufficient to target that locus to the nuclear periphery, allowing identification of a minimal portion of Gcn4 that is necessary and sufficient to promote interaction with Nups. This strategy identified a positioning domain within the Gcn4 TF (PDGCN4), a 27 amino acid peptide, separable from the activation domains. Mutation of three amino acids within this sequence disrupts interaction of Gcn4 target genes with the NPC and results in a global defect in transcriptional activation of Gcn4 target genes (Brickner et al. 2019). Tethering of the PDGCN4 to an ectopic locus led to interaction with Nup2, but not with coactivators like SAGA or Mediator. These results argue that Nup interaction can enhance activator domain-dependent transcription, but cannot activate transcription in the absence of an activator domain.

Interaction with metazoan Nups can also positively regulate transcription (Fig. 2B). Knockdown of Nups in flies leads to widespread decrease in transcription (Capelson et al. 2010). Likewise, loss of Nup98 in embryonic stem cells impacts transcription and developmental potential (Liang et al. 2013a) and loss of the tissue-specific Nup210 inhibits proper muscle cell gene expression and differentiation (D'Angelo et al. 2012; Raices et al. 2017). Although Nups interact throughout the genome, they bind strongly at super-enhancers (Ibarra et al. 2016). These effects correlate with impacts on chromatin folding and structure. Interaction with Nups facilitates recruitment of cohesin and formation of topologically associated domains (TADs) as well as promoter–enhancer looping (Pascual-Garcia et al. 2017; Kadota et al. 2020). Tethering of Nups such as Sec13 or Elys to polytene chromosomes in Drosophila leads to chromatin decondensation (Fig. 2B; Kuhn et al. 2019). The tethered Nups recruit PBAP/Brm and GAGA, which are required for decondensation (Kuhn et al. 2019). Thus, the role of Nups in animals in promoting transcription may relate to their effects on chromatin folding and condensation.

The NPC's role in interacting with chromatin to modulate transcription has also been explored in plants. In Arabidopsis thaliana, tethering of the Nup Seh1 to a reporter transgene caused positioning at the nuclear periphery and stimulated transcription (Smith et al. 2015). Likewise, Arabidopsis Nup1 is necessary for pollen and ovule development, and loss of Nup1 leads to a significant decrease in the expression of gametogenesis genes, although it is unknown whether these genes physically interact with the NPC (Bao et al. 2019). Also, the chlorophyll a/b gene locus undergoes light-dependent repositioning from the nuclear interior to the nuclear periphery upon transcriptional activation (Feng et al. 2014). However, a connection to the NPC has not been explored and this repositioning requires a set of proteins not implicated in yeast or metazoan gene positioning, raising the possibility that other mechanisms impact localization to the nuclear periphery in plants.

THE NPC AS A REGULATOR OF EPIGENETIC MEMORY

Nups interact with both active and silent loci and can promote both transcription and repression. But Nups also play a conserved role in a type of epigenetic poising following specific expression states. In yeast, the INO1 locus is targeted to the NPC both when active and when recently repressed (Brickner et al. 2007). This latter state is called “transcriptional memory” and is inherited for several generations. The molecular mechanism for targeting (i.e., the TFs, the cis-acting zip codes, and the Nups required) of active INO1 and recently repressed INO1 are different (Fig. 2C; Light et al. 2010). Whereas active INO1 is targeted to the NPC by the gene recruitment sequences GRS1 and GRS2 and the TFs Put3 and Cbf1, recently repressed INO1 is targeted to the NPC by the memory recruitment sequence (MRS), which binds the Sfl1 TF.

Furthermore, memory requires chromatin modifications and Nup100, both of which are not required for recruiting active INO1 to the periphery (Brickner et al. 2007; Light et al. 2010; D'Urso et al. 2016). This suggests that there are at least two mechanisms by which genes interact with the NPC in yeast, one that requires Nup100 and one that does not. This conclusion is bolstered by the finding that, while tethering of 121 yeast TFs to a chromosomal site is sufficient to cause Nup2-dependent targeting to the nuclear periphery, only 76 of those TFs also require Nup100 (Brickner et al. 2019).

Transcriptional memory leads to changes in the chromatin state of the promoter, allowing the recruitment of a poised form of RNA polymerase II preinitiation complex (RNAPII PIC). This poised state of the promoter is activated more rapidly than it would be otherwise, presumably providing an adaptive fitness advantage. In the case of the INO1 gene, loss of Sfl1, the MRS, or Nup100 blocks memory, leading to slower reactivation. Thus, the same locus can be targeted to the NPC by two distinct mechanisms, producing two distinct outcomes, depending on the state and history of the cell.

The phenomenon of yeast transcriptional memory is widespread. In yeast, many genes exhibit an enhanced activation rate if previously expressed, which can enhance adaptive fitness (Sood and Brickner 2017). Furthermore, memory is generally associated with changes in chromatin modifications (H2A.Z incorporation, H3 lysine 4 dimethylation [H4K4me2]) and recruitment of a novel, poised RNA polymerase II preinitation complex (Fig. 2C; D'Urso et al. 2016; Sood et al. 2017). However, it does not always require interaction with the NPC, suggesting that the interaction with the NPC regulates a core memory mechanism involving chromatin changes and promoter poising.

Nup-dependent memory has also been observed in metazoan cells. In HeLa cells, genes induced by interferon γ (IFN-γ) interact with Nup98 (the Nup100 homolog) upon removal of IFN-γ, and this interaction persists for >4 days. These genes show faster/more robust expression if cells are exposed to IFN-γ again. Promoters of such poised genes are marked with H3K4me2 and bind RNA polymerase II. Transient knockdown of Nup98 during memory led to a loss of H3K4me2 and RNA polymerase II from promoters and disrupted the faster rate of reactivation (Light et al. 2013). Thus, Nups have an ancient, conserved role in controlling chromatin states that facilitate epigenetic transcriptional regulation.

In flies, ecdysone-induced genes also interact with Nup98 and exhibit transcriptional memory. Brief exposure of S2 cells to ecdysone leads to Nup98 binding and poises target genes for induction (Pascual-Garcia et al. 2017). The knockdown of Nup98 specifically disrupts this effect, leading to no memory. The effect of Nup98 in this system (and perhaps others) is to stabilize a promoter–enhancer loop. This loop is strengthened by previous treatment with ecdysone and by binding to Nup98, suggesting that Nup98-dependent chromatin folding can facilitate the establishment and inheritance of epigenetic states.

The impact of Nups on chromatin and transcription also has important effects on human health. Chromosomal translocations that lead to translational fusions of Nup98 with several proteins such as HOXA9, HOXD13, Top1, and Nsd1 lead to acute myeloid leukemia (AML) (Franks et al. 2017). Why? Nup98 is associated with H3K4 methylation in flies and humans and interacts with the H3K4 methyltransferases Trithorax and MLL1, respectively (Fig. 2C; Kaltenbach et al. 2010; Gough et al. 2011; Pascual-Garcia et al. 2014). This led to the hypothesis that AML is due to excessive H3K4 methylation of target genes induced by ectopic recruitment of Nup98 at those loci (Franks et al. 2017). Indeed, the Nup98-Nsd1 fusion protein expressed in myeloid cells from AML patients binds to Wdr82, a component of the H3K4 methyltransferase Set1A/B-COMPASS. Forming this aberrant complex results in transcription-associated histone modifications at Nsd1 target genes, such as the HOXA locus, and leads to an increase in expression (Michmerhuizen et al. 2020). These findings show the critical role of Nup98/Nup100 in epigenetic regulation in regulating normal and pathogenic transcription.

CLOSING REMARKS

The NPC is an ancient structural component of eukaryotic cells. In addition to mediating nucleocytoplasmic trafficking, a role for nuclear pore proteins in regulating transcription and chromatin structure is now appreciated. Additionally, the interaction of the NPC with the genome impacts its spatial arrangement. Specific interactions between genes and Nups are associated with transcriptional silencing, transcriptional activation, transcriptional poising, changes in chromatin modifications and changes in chromatin folding. While the field is still exploring the precise molecular nature of these roles, it is clear that the NPC impacts genome function and gene expression and multiple levels.

ACKNOWLEDGMENTS

We would like to acknowledge our colleagues cited herein for their contributions to the field and the editors of this edition for their patience. M.C.S. was supported by National Institutes of Health (NIH) Grant T32 GM008061. M.C.S. and J.B. were supported by NIH Grants R01 GM118712 (to J.B.) and R35 GM136419 (to J.B.).

Footnotes

Editors: Ana Pombo, Martin W. Hetzer, and Tom Misteli

Additional Perspectives on The Nucleus available at www.cshperspectives.org

REFERENCES

  1. Ahmed S, Brickner DG, Light WH, Cajigas I, McDonough M, Froyshteter AB, Volpe T, Brickner JH. 2010. DNA zip codes control an ancient mechanism for gene targeting to the nuclear periphery. Nat Cell Biol 12: 111–118. 10.1038/ncb2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bao S, Shen G, Li G, Liu Z, Arif M, Wei Q, Men S. 2019. The Arabidopsis nucleoporin NUP1 is essential for megasporogenesis and early stages of pollen development. Plant Cell Rep 38: 59–74. 10.1007/s00299-018-2349-7 [DOI] [PubMed] [Google Scholar]
  3. Blobel G. 1985. Gene gating: a hypothesis. Proc Natl Acad Sci 82: 8527–8529. 10.1073/pnas.82.24.8527 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boumendil C, Hari P, Olsen KCF, Acosta JC, Bickmore WA. 2019. Nuclear pore density controls heterochromatin reorganization during senescence. Gene Dev 33: 144–149. 10.1101/gad.321117.118 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brickner JH, Walter P. 2004. Gene recruitment of the activated INO1 locus to the nuclear membrane. Plos Biol 2: e342. 10.1371/journal.pbio.0020342 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brickner DG, Cajigas I, Fondufe-Mittendorf Y, Ahmed S, Lee PC, Widom J, Brickner JH. 2007. H2a.Z-mediated localization of genes at the nuclear periphery confers epigenetic memory of previous transcriptional state. Plos Biol 5: e81. 10.1371/journal.pbio.0050081 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brickner DG, Ahmed S, Meldi L, Thompson A, Light W, Young M, Hickman TL, Chu F, Fabre E, Brickner JH. 2012. Transcription factor binding to a DNA zip code controls interchromosomal clustering at the nuclear periphery. Dev Cell 22: 1234–1246. 10.1016/j.devcel.2012.03.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brickner DG, Sood V, Tutucci E, Coukos R, Viets K, Singer RH, Brickner JH. 2016. Subnuclear positioning and interchromosomal clustering of the GAL1-10 locus are controlled by separable, interdependent mechanisms. Mol Biol Cell 27: 2980–2993. 10.1091/mbc.E16-03-0174 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Brickner DG, Randise-Hinchliff C, Corbin ML, Liang JM, Kim S, Sump B, D'Urso A, Kim SH, Satomura A, Schmit H, et al. 2019. The role of transcription factors and nuclear pore proteins in controlling the spatial organization of the yeast genome. Dev Cell 49: 936–947.e4. 10.1016/j.devcel.2019.05.023 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Brown JM, Green J, das Neves RP, Wallace HA, Smith AJ, Hughes J, Gray N, Taylor S, Wood WG, Higgs DR, et al. 2008. Association between active genes occurs at nuclear speckles and is modulated by chromatin environment. J Cell Biol 182: 1083–1097. 10.1083/jcb.200803174 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cabal GG, Genovesio A, Rodriguez-Navarro S, Zimmer C, Gadal O, Lesne A, Buc H, Feuerbach-Fournier F, Olivo-Marin JC, Hurt EC, et al. 2006. SAGA interacting factors confine sub-diffusion of transcribed genes to the nuclear envelope. Nature 441: 770–773. 10.1038/nature04752 [DOI] [PubMed] [Google Scholar]
  12. Callan HG, Tomlin SG. 1950. 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 137: 367–378. [DOI] [PubMed] [Google Scholar]
  13. Capelson M, Liang Y, Schulte R, Mair W, Wagner U, Hetzer MW. 2010. Chromatin-bound nuclear pore components regulate gene expression in higher eukaryotes. Cell 140: 372–383. 10.1016/j.cell.2009.12.054 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Casolari JM, Brown CR, Komili S, West J, Hieronymus H, Silver PA. 2004. Genome-wide localization of the nuclear transport machinery couples transcriptional status and nuclear organization. Cell 117: 427–439. 10.1016/S0092-8674(04)00448-9 [DOI] [PubMed] [Google Scholar]
  15. Casolari JM, Brown CR, Drubin DA, Rando OJ, Silver PA. 2005. Developmentally induced changes in transcriptional program alter spatial organization across chromosomes. Genes Dev 19: 1188–1198. 10.1101/gad.1307205 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. D'Angelo MA, Gomez-Cavazos JS, Mei A, Lackner DH, Hetzer MW. 2012. A change in nuclear pore complex composition regulates cell differentiation. Dev Cell 22: 446–458. 10.1016/j.devcel.2011.11.021 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Dieppois G, Iglesias N, Stutz F. 2006. Cotranscriptional recruitment to the mRNA export receptor Mex67p contributes to nuclear pore anchoring of activated genes. Mol Cell Biol 26: 7858–7870. 10.1128/MCB.00870-06 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. D'Urso A, Takahashi Y, Xiong B, Marone J, Coukos R, Randise-Hinchliff C, Wang J-P, Shilatifard A, Brickner JH. 2016. Set1/COMPASS and Mediator are repurposed to promote epigenetic transcriptional memory. eLife 5: e16691. 10.7554/eLife.16691 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Falk M, Feodorova Y, Naumova N, Imakaev M, Lajoie BR, Leonhardt H, Joffe B, Dekker J, Fudenberg G, Solovei I, et al. 2019. Heterochromatin drives compartmentalization of inverted and conventional nuclei. Nature 570: 395–399. 10.1038/s41586-019-1275-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Feng CM, Qiu Y, Buskirk EKV, Yang EJ, Chen M. 2014. Light-regulated gene repositioning in Arabidopsis. Nat Commun 5: 3027. 10.1038/ncomms4027 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Feuerbach F, Galy V, Trelles-Sticken E, Fromont-Racine M, Jacquier A, Gilson E, Olivo-Marin JC, Scherthan H, Nehrbass U. 2002. Nuclear architecture and spatial positioning help establish transcriptional states of telomeres in yeast. Nat Cell Biol 4: 214–221. 10.1038/ncb756 [DOI] [PubMed] [Google Scholar]
  22. Franks TM, McCloskey A, Shokirev MN, Benner C, Rathore A, Hetzer MW. 2017. Nup98 recruits the Wdr82-Set1 A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells. Gene Dev 31: 2222–2234. 10.1101/gad.306753.117 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Gall JG. 1967. Octagonal nuclear pores. J Cell Biol 32: 391–399. 10.1083/jcb.32.2.391 [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Galy V, Olivo-Marin JC, Scherthan H, Doye V, Rascalou N, Nehrbass U. 2000. Nuclear pore complexes in the organization of silent telomeric chromatin. Nature 403: 108–112. 10.1038/47528 [DOI] [PubMed] [Google Scholar]
  25. Goldberg MW, Allen TD. 1992. High resolution scanning electron microscopy of the nuclear envelope: demonstration of a new, regular, fibrous lattice attached to the baskets of the nucleoplasmic face of the nuclear pores. J Cell Biol 119: 1429–1440. 10.1083/jcb.119.6.1429 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Gotta M, Laroche T, Formenton A, Maillet L, Scherthan H, Gasser SM. 1996. The clustering of telomeres and colocalization with Rap1, Sir3, and Sir4 proteins in wild-type Saccharomyces cerevisiae. J Cell Biol 134: 1349–1363. 10.1083/jcb.134.6.1349 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Gottschling DE, Aparicio OM, Billington BL, Zakian VA. 1990. Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell 63: 751–762. 10.1016/0092-8674(90)90141-Z [DOI] [PubMed] [Google Scholar]
  28. Gough SM, Slape CI, Aplan PD. 2011. NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights. Blood 118: 6247–6257. 10.1182/blood-2011-07-328880 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Gozalo A, Duke A, Lan Y, Pascual-Garcia P, Talamas JA, Nguyen SC, Shah PP, Jain R, Joyce EF, Capelson M. 2020. Core components of the nuclear pore bind distinct states of chromatin and contribute to Polycomb repression. Mol Cell 77: 67–81.e7. 10.1016/j.molcel.2019.10.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Green EM, Jiang Y, Joyner R, Weis K. 2012. A negative feedback loop at the nuclear periphery regulates GAL gene expression. Mol Biol Cell 23: 1367–1375. 10.1091/mbc.e11-06-0547 [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Griffis ER, Altan N, Lippincott-Schwartz J, Powers MA. 2002. Nup98 is a mobile nucleoporin with transcription-dependent dynamics. Mol Biol Cell 13: 1282–1297. 10.1091/mbc.01-11-0538 [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Guglielmi V, Sakuma S, D'Angelo MA. 2020. Nuclear pore complexes in development and tissue homeostasis. Development 147: dev183442. 10.1242/dev.183442 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Hope IA, Struhl K. 1985. GCN4 protein, synthesized in vitro, binds HIS3 regulatory sequences: implications for general control of amino acid biosynthetic genes in yeast. Cell 43: 177–188. 10.1016/0092-8674(85)90022-4 [DOI] [PubMed] [Google Scholar]
  34. Ibarra A, Benner C, Tyagi S, Cool J, Hetzer MW. 2016. Nucleoporin-mediated regulation of cell identity genes. Gene Dev 30: 2253–2258. 10.1101/gad.287417.116 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Jacinto FV, Benner C, Hetzer MW. 2015. The nucleoporin Nup153 regulates embryonic stem cell pluripotency through gene silencing. Gene Dev 29: 1224–1238. 10.1101/gad.260919.115 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Jani D, Valkov E, Stewart M. 2014. Structural basis for binding the TREX2 complex to nuclear pores, GAL1 localisation and mRNA export. Nucleic Acids Res 42: 6686–6697. 10.1093/nar/gku252 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Jost KL, Bertulat B, Cardoso MC. 2012. Heterochromatin and gene positioning: inside, outside, any side? Chromosoma 121: 555–563. 10.1007/s00412-012-0389-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Kadota S, Ou J, Shi Y, Lee JT, Sun J, Yildirim E. 2020. Nucleoporin 153 links nuclear pore complex to chromatin architecture by mediating CTCF and cohesin binding. Nat Commun 11: 2606. 10.1038/s41467-020-16394-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Kaltenbach S, Soler G, Barin C, Gervais C, Bernard OA, Penard-Lacronique V, Romana SP. 2010. NUP98-MLL fusion in human acute myeloblastic leukemia. Blood 116: 2332–2335. 10.1182/blood-2010-04-277806 [DOI] [PubMed] [Google Scholar]
  40. Kalverda B, Pickersgill H, Shloma VV, Fornerod M. 2010. Nucleoporins directly stimulate expression of developmental and cell-cycle genes inside the nucleoplasm. Cell 140: 360–371. 10.1016/j.cell.2010.01.011 [DOI] [PubMed] [Google Scholar]
  41. Kuhn TM, Pascual-Garcia P, Gozalo A, Little SC, Capelson M. 2019. Chromatin targeting of nuclear pore proteins induces chromatin decondensation. J Cell Biol 218: 2945–2961. 10.1083/jcb.201807139 [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Lapetina DL, Ptak C, Roesner UK, Wozniak RW. 2017. Yeast silencing factor Sir4 and a subset of nucleoporins form a complex distinct from nuclear pore complexes. J Cell Biol 216: 3145–3159. 10.1083/jcb.201609049 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Larsson AJM, Johnsson P, Hagemann-Jensen M, Hartmanis L, Faridani OR, Reinius B, Segerstolpe Å, Rivera CM, Ren B, Sandberg R. 2019. Genomic encoding of transcriptional burst kinetics. Nature 565: 251–254. 10.1038/s41586-018-0836-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Liang Y, Franks TM, Marchetto MC, Gage FH, Hetzer MW. 2013a. Dynamic association of NUP98 with the human genome. PLoS Genet 9: e1003308. 10.1371/journal.pgen.1003308 [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Liang Y, Franks TM, Marchetto MC, Gage FH, Hetzer MW. 2013b. Dynamic association of NUP98 with the human genome. Plos Genet 9: e1003308. 10.1371/journal.pgen.1003308 [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Light WH, Brickner DG, Brand VR, Brickner JH. 2010. Interaction of a DNA zip code with the nuclear pore complex promotes H2A.Z incorporation and INO1 transcriptional memory. Mol Cell 40: 112–125. 10.1016/j.molcel.2010.09.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Light WH, Freaney J, Sood V, Thompson A, D'Urso A, Horvath CM, Brickner JH. 2013. A conserved role for human Nup98 in altering chromatin structure and promoting epigenetic transcriptional memory. Plos Biol 11: e1001524. 10.1371/journal.pbio.1001524 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Luthra R, Kerr SC, Harreman MT, Apponi LH, Fasken MB, Ramineni S, Chaurasia S, Valentini SR, Corbett AH. 2007. Actively transcribed GAL genes can be physically linked to the nuclear pore by the SAGA chromatin modifying complex. J Biol Chem 282: 3042–3049. 10.1074/jbc.M608741200 [DOI] [PubMed] [Google Scholar]
  49. Michmerhuizen NL, Klco JM, Mullighan CG. 2020. Mechanistic insights and potential therapeutic approaches for NUP98-rearranged hematologic malignancies. Blood 136: 2275–2289. 10.1182/blood.2020007093 [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Misteli T. 2020. The self-organizing genome: principles of genome architecture and function. Cell 183: 28–45. 10.1016/j.cell.2020.09.014 [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Pascual-Garcia P, Jeong J, Capelson M. 2014. Nucleoporin Nup98 associates with Trx/MLL and NSL histone-modifying complexes and regulates Hox gene expression. Cell Rep 9: 433–442. 10.1016/j.celrep.2014.09.002 [DOI] [PubMed] [Google Scholar]
  52. Pascual-Garcia P, Debo B, Aleman JR, Talamas JA, Lan Y, Nguyen NH, Won KJ, Capelson M. 2017. Metazoan nuclear pores provide a scaffold for poised genes and mediate induced enhancer–promoter contacts. Mol Cell 66: 63–76.e6. 10.1016/j.molcel.2017.02.020 [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Raices M, Bukata L, Sakuma S, Borlido J, Hernandez LS, Hart DO, D'Angelo MA. 2017. Nuclear pores regulate muscle development and maintenance by assembling a localized Mef2C complex. Dev Cell 41: 540–554.e7. 10.1016/j.devcel.2017.05.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Randise-Hinchliff C, Coukos R, Sood V, Sumner MC, Zdraljevic S, Sholl LM, Brickner DG, Ahmed S, Watchmaker L, Brickner JH. 2016. Strategies to regulate transcription factor–mediated gene positioning and interchromosomal clustering at the nuclear periphery. J Cell Biol 212: 633–646. 10.1083/jcb.201508068 [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Rawal Y, Chereji RV, Valabhoju V, Qiu H, Ocampo J, Clark DJ, Hinnebusch AG. 2018. Gcn4 binding in coding regions can activate internal and canonical 5′ promoters in yeast. Mol Cell 70: 297–311.e4. 10.1016/j.molcel.2018.03.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Rodriguez J, Larson DR. 2020. Transcription in living cells: molecular mechanisms of bursting. Annu Rev Biochem 89: 189–212. 10.1146/annurev-biochem-011520-105250 [DOI] [PubMed] [Google Scholar]
  57. Schmid M, Arib G, Laemmli C, Nishikawa J, Durussel T, Laemmli UK. 2006. Nup-PI: the nucleopore–promoter interaction of genes in yeast. Mol Cell 21: 379–391. 10.1016/j.molcel.2005.12.012 [DOI] [PubMed] [Google Scholar]
  58. Smith S, Galinha C, Desset S, Tolmie F, Evans D, Tatout C, Graumann K. 2015. Marker gene tethering by nucleoporins affects gene expression in plants. Nucleus 6: 471–478. 10.1080/19491034.2015.1126028 [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Sood V, Brickner JH. 2017. Genetic and epigenetic strategies potentiate Gal4 activation to enhance fitness in recently diverged yeast species. Curr Biol 27: 3591–3602.e3. 10.1016/j.cub.2017.10.035 [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Sood V, Cajigas I, D'Urso A, Light WH, Brickner JH. 2017. Epigenetic transcriptional memory of GAL genes depends on growth in glucose and the Tup1 transcription factor in Saccharomyces cerevisiae. Genetics 206: 1895–1907. 10.1534/genetics.117.201632 [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Texari L, Dieppois G, Vinciguerra P, Contreras MP, Groner A, Letourneau A, Stutz F. 2013. The nuclear pore regulates GAL1 gene transcription by controlling the localization of the SUMO protease Ulp1. Mol Cell 51: 807–818. 10.1016/j.molcel.2013.08.047 [DOI] [PubMed] [Google Scholar]
  62. Tunnacliffe E, Corrigan AM, Chubb JR. 2018. Promoter-mediated diversification of transcriptional bursting dynamics following gene duplication. Proc National Acad Sci 115: 8364–8369. 10.1073/pnas.1800943115 [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Van de Vosse DW, Wan Y, Lapetina DL, Chen WM, Chiang JH, Aitchison JD, Wozniak RW. 2013. A role for the nucleoporin Nup170p in chromatin structure and gene silencing. Cell 152: 969–983. 10.1016/j.cell.2013.01.049 [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. von Appen A, Beck M. 2016. Structure determination of the nuclear pore complex with three-dimensional cryo electron microscopy. J Mol Biol 428: 2001–2010. 10.1016/j.jmb.2016.01.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Watson ML. 1955. The nuclear envelope its structure and relation to cytoplasmic membranes. J Biophys Biochem Cytol 1: 257–270. 10.1083/jcb.1.3.257 [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Weiler KS, Wakimoto BT. 1995. Heterochromatin and gene expression in Drosophila. Annu Rev Genet 29: 577–605. 10.1146/annurev.ge.29.120195.003045 [DOI] [PubMed] [Google Scholar]
  67. Zykova TY, Levitsky VG, Belyaeva ES, Zhimulev IF. 2018. Polytene chromosomes—a portrait of functional organization of the Drosophila genome. Curr Genomics 19: 179–191. 10.2174/1389202918666171016123830 [DOI] [PMC free article] [PubMed] [Google Scholar]

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