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The new nucleoporin: regulator of transcriptional repression and beyond.
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PMID:  23047597     Owner:  NLM     Status:  MEDLINE    
Transcriptional regulation is a complex process that requires the integrated action of many multi-protein complexes. The way in which a living cell coordinates the action of these complexes in time and space is still poorly understood. Recent work has shown that nuclear pores, well known for their role in 3' processing and export of transcripts, also participate in the control of transcriptional initiation. We have recently begun to explore how nuclear pores interface with the well-described machinery that regulates initiation. This work led to the discovery that specific nucleoporins are required for binding of the repressor protein Mig1 to its site in target promoters. Nuclear pores are therefore involved in repressing, as well as activating, transcription. Here we discuss in detail the main models explaining our result and consider what each implies about the roles that nuclear pores play in the regulation of gene expression.
Nayan J Sarma; Kristine Willis
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-10-09
Journal Detail:
Title:  Nucleus (Austin, Tex.)     Volume:  3     ISSN:  1949-1042     ISO Abbreviation:  Nucleus     Publication Date:    2012 Nov-Dec
Date Detail:
Created Date:  2012-11-30     Completed Date:  2013-05-09     Revised Date:  2014-10-10    
Medline Journal Info:
Nlm Unique ID:  101518322     Medline TA:  Nucleus     Country:  United States    
Other Details:
Languages:  eng     Pagination:  508-15     Citation Subset:  IM    
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MeSH Terms
Gene Expression Regulation, Fungal
Histones / metabolism
Homeodomain Proteins / metabolism
Models, Molecular
Nuclear Pore / metabolism
Nuclear Pore Complex Proteins / genetics,  metabolism*
Promoter Regions, Genetic
Repressor Proteins / genetics,  metabolism
Saccharomyces cerevisiae / genetics,  metabolism
Saccharomyces cerevisiae Proteins / genetics,  metabolism*
beta-Fructofuranosidase / genetics,  metabolism
Grant Support
Reg. No./Substance:
0/Histones; 0/Homeodomain Proteins; 0/MIG1 protein, S cerevisiae; 0/NUP120 protein, S cerevisiae; 0/NUP133 protein, S cerevisiae; 0/Nuclear Pore Complex Proteins; 0/Repressor Proteins; 0/Saccharomyces cerevisiae Proteins; 0/homeobox protein HOXA9; 0/nuclear pore complex protein 98; EC protein, S cerevisiae; EC

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Journal Information
Journal ID (nlm-ta): Nucleus
Journal ID (iso-abbrev): Nucleus
Journal ID (publisher-id): NUCL
ISSN: 1949-1034
ISSN: 1949-1042
Publisher: Landes Bioscience
Article Information
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Copyright © 2012 Landes Bioscience
Print publication date: Day: 01 Month: 11 Year: 2012
pmc-release publication date: Day: 01 Month: 11 Year: 2012
Volume: 3 Issue: 6
First Page: 508 Last Page: 515
PubMed Id: 23047597
ID: 3515533
Publisher Id: 2011NUCLEUS0108R
Publisher Item Identifier: 22427
DOI: 10.4161/nucl.22427

The new nucleoporin : Regulator of transcriptional repression and beyond
Nayan J. Sarma1
Kristine Willis2*
1Department of Surgery; Washington University School of Medicine; St. Louis, MO USA
2Department of Biology; Georgetown University; Washington, DC USA
*Correspondence to: Kristine Willis, Email:


Cells respond to environmental cues to grow and differentiate by turning discrete sets of genes on and off. Although no one model appears to apply to all genes,1,2 work done over the past 40 y has given us a general understanding of how a eukaryotic cell accomplishes this on/off switch.2-9 The process is complex, requiring the interaction of nucleosomes, chromatin remodelers, chromatin modifiers, sequence-specific repressors and activators, co-activators, basal transcription factors, positive and negative regulators of elongation, termination factors and of course the DNA itself. Control of transcriptional initiation, though historically appreciated as important, is only one way in which information in the genome is managed. Once the signal to express a certain gene has been received and the necessary factors are all associated with the DNA, the polymerase must escape from the promoter and transition to productive elongation, travel down the body of the gene and stop correctly once the termination signal has been reached. At the same time, the mRNA must be capped, spliced and polyadenylated, then exported to the cytoplasm for translation when finished. Each step in this process is highly interdependent and subject to multiple levels of regulation.2,10-12 Developing a precise understanding of the mechanisms that enforce these multiple levels of regulation and the ways in which they interact with each other is now the central challenge in the field of gene expression.

Recently, it has been shown that several different subunits of the nuclear pore, a 60 MDa complex best known for its role in nucleocytoplasmic transport, also play a role in upstream transcriptional regulation. Nuclear pore proteins (nucleoporins) have been found in physical association with both active and repressed regions of the budding yeast, fruit fly, rat and human genomes.13-21 Importantly, a subset of nucleoporins interact with DNA in the nuclear interior, independently of the presence of RNA polymerase II. This finding strongly suggests that proteins of the nuclear pore play a role in transcription that is independent of mRNA transport.19,20 Consistent with such a role, experiments in both flies and rats have shown that knock-down or overexpression of nucleoporins reciprocally alters mRNA levels of the genes with which they interact.14,15,19,20,22 However, almost nothing is known about the nature of the nuclear pore-genome interaction, or the mechanics of how nucleoporins contribute to transcriptional regulation.

Recently, though, we have identified a specific mechanism through which nuclear pore proteins can influence transcription. Deletion of either of two particular subunits of the nuclear pore, NUP120 or NUP133, results in a loss of repression of SUC2, one of the canonical model genes in the Saccharomyces cerevisiae system on which our current understanding of transcriptional regulation has been built. This loss of repression is not attributable to defects in the nucleocytoplasmic shuttling of Mig1, the DNA-binding factor primarily responsible for inhibition of SUC2 transcription. Instead, nuclear Mig1 must physically associate with intact nuclear pore complexes (NPCs) in order to bind DNA and repress transcription. In other words, the ability of the repressor to find its site in the DNA is dependent on its interaction with NPCs; both interaction with NPCs and DNA binding are lost if either NUP120 or NUP133 is deleted. Viewed in the context of earlier work, this result suggests that nuclear pore proteins function as transcriptional regulators by exerting a global influence on chromatin biology, nuclear organization, or both.

Different Biological Functions for Nuclear Pores

Nuclear pores were first identified as electron-dense structures visible in microscopic analyses of the nuclear membrane performed during the 1950s.23-28 Over the next 25 y, their universality in eukaryotic cells, as well as a consensus regarding their overall shape and size, became well established. By 1975 two distinct but mutually compatible functions of nuclear pores had been proposed: nucleocytoplasmic transport and chromatin organization.29 NPCs are now known to be the sole conduit through which macromolecules are exchanged between the nucleus and cytoplasm (reviewed in refs. 30 and 31). The second postulated function, which was predicated on numerous observations of the physical proximity of chromatin to nuclear pores,32-39 has received less attention. Recent work, though, has reintroduced the idea that this physical juxtaposition may indicate a functional link.

ChIP,13-15,40 ChIP-chip16-19 and chromatin cleavage20,41 analyses have shown that subunits of the nuclear pore, or nucleoporins, interact with both active and inactive regions of the genomes of budding yeast, fruit flies, rats and humans (Table 1). Several lines of evidence suggest that these interactions serve a purpose other than facilitating the export of newly synthesized transcripts. First and simplest, some nucleoporins preferentially associate with regions of the genome that are not transcribed.14,18 The next argument for a transport-independent function stems from the observation that some nucleoporins localize to both the nuclear periphery and the nuclear interior,42-46 also called the nucleoplasm; nucleoplasmic pools of these nucleoporins have been shown to interact with loci that are also found in the nuclear interior and to influence steady-state levels of mRNA transcribed from these genes.14,19,20 Finally, work done in fruit flies has directly demonstrated that the association between nucleoporins and active genes is stable to treatment with RNase A and thus not tethered by RNA molecules in the process of being exported.14

Since RNA-only models are ruled out, the way in which nucleoporins interact with the genome is unclear. With one possible exception,47 nucleoporins do not contain recognizable domains for binding DNA or chromatin directly. It therefore seems likely that they recognize specific loci through another protein or proteins, but the identity of these is currently unknown. However, examining the function of nucleoporin-DNA interactions may provide a hint about mechanism of interaction. In budding yeast, nucleoporins interact specifically with intergenic regions, places where the transcriptional machinery and the DNA first come into contact; this contact occurs independently of active transcription.13,41 Two Drosophila nucleoporins, Nup98 and Sec13, have been shown to make contact with their target loci prior to RNA polymerase.14 Consistent with these data, the yeast nucleoporin Nup2 has been shown to contact the promoter of the GAL1,10 locus prior to TBP.41 Sequence specific transcription factors, chromatin remodelers and chromatin modifying complexes are therefore the most logical candidates for proteins that serve as intermediates between nucleoporins and DNA, since only they arrive at the promoter prior to TBP.

Regulation of SUC2 Transcription is Linked to Nuclear Pores

Our understanding of glucose-regulated gene expression in the model eukaryote Saccharomyces cerevisiae has been established largely through study of the SUC2 promoter. Work completed over the past 25 y has thoroughly identified the set of proteins that control its activity (Fig. 1), although the way in which they work together is still not fully understood. Two factors central to this regulatory system are the Snf1 kinase and the DNA-binding repressor protein Mig1. Together they control transcription of not only SUC2, but approximately 300 other genes.48

Recent work has shown that the promoters of three Mig1 targets—SUC2, HXK1 and GAL1, 1013,41—are also bound by nuclear pore proteins; furthermore, these genes very likely spend some time interacting with intact NPCs, since GFP tagging shows they periodically visit the nuclear periphery when repressed and localize there for prolonged intervals when active.13,49,50 We therefore wondered if the Snf1 and Mig1 proteins themselves might also interact with NPCs. We found that Snf1 co-fractionates with intact NPCs only in the absence of glucose, when SUC2, HXK1 and GAL1,10 are actively transcribed and stably associated with nuclear pores. In contrast, Mig1 co-fractionates with NPCs only in the presence of glucose, when these three target genes are repressed and appear to interact with nuclear pores transiently.13 However, Snf1 and Mig1 undergo nucleocytoplasmic transport in response to changes in the availability of glucose and must associate with the nuclear pores for this purpose. Both proteins cross the pore when glucose appears as well as when it disappears; therefore it is not straightforward to explain the differential physical association we observe by invoking a transport-only function, but we still considered it a possibility. Accordingly, we looked for a way to test whether the association of these regulators with nuclear pores was only a reflection of their transport. It has long been known that deletion of HXK2, which encodes the predominant form of hexokinase in budding yeast, causes defects in Mig1-dependent glucose repression.51-53 We found that in an hxk2∆ mutant, Mig1 is properly localized to the nucleus in response to the appearance of glucose; however, despite being localized to the nucleus in this mutant, Mig1 no longer co-fractionates with nuclear pores.13 In other words, our analysis of an hxk2∆ mutant shows that repressor function of Mig1 requires its physical association with NPCs in a way that is independent of the protein’s nucleocytoplasmic transport.

Specific subunits of the NPC Mediate Binding of the Mig1 Repressor to Target Promoters

We next asked whether mutation of nuclear pores themselves might cause defects in the transcriptional regulation of SUC2. Of particular interest were cells deleted for either NUP120 or NUP133, in which we observed a loss of repression of SUC2 approximately equal to that seen on deleting MIG1 itself.54 Since a reduction in export of SUC2 mRNA would not be expected to lead to an increase in levels of the translated protein product, we reasoned that these nucleoporins likely impact regulation of SUC2 expression at the level of transcription. Visualization of Mig1-GFP shows that import of Mig1 into the nucleus does not require Nup120 or Nup133.54 Given our above-described data on Hxk2, though, we wondered if Nup120 and Nup133 might be required for the interaction of Mig1 with NPCs. We found that this is true; although Mig1 is correctly transported into and out of the nucleus in the absence of these nucleoporins, it is no longer able to co-fractionate with nuclear pores. In the absence of Nup120 or Nup133, nuclear Mig1 is also unable to bind its site in DNA.54 This striking result provides a clear explanation of how these nucleoporins influence SUC2 repression.

How Nuclear Pores Might Influence Gene Expression: Models and Possible Mechanisms

Why does MIg1 require Nup120 and Nup133 to bind DNA? We have shown that Mig1 co-purifies with intact NPCs in glucose-grown cells, in which the repressor binds its target loci.13,54 We have also shown that both Nup133 and Pom152 interact with the SUC2 promoter in glucose-grown cells.54 Nup133 is a structural component of the NPC, and Pom152 is an integral nuclear membrane protein. We therefore interpret this result to mean that in the presence of glucose, the repressed SUC2 promoter makes transient contact with intact NPCs embedded in the nuclear membrane. This interpretation is consistent with the observation that the SUC2 locus can be seen to periodically “visit” the nuclear periphery in glucose grown cells.13 An obvious possibility, therefore, is that during these visits, the NPC facilitates binding of the repressor protein to the DNA by simultaneously interacting with both. Bringing together a gene and its transcriptional regulator in a particular location, at the nuclear periphery, might not only facilitate DNA binding, but also reduce the time it takes that transcription factor to search the genome for its site.

Drawing the simplest possible analogy to cooperative DNA binding by two transcription factors (Fig. 2A), we can infer two significant corollaries to this model. First, SUC2 is required to contact the NPC independently of Mig1. As noted above, this second, Mig1-independent contact may be direct, but more likely occurs through some other, currently unidentified factor. Second, deletion of any one of the components shown in Figure 2A has the potential to reduce the affinity with which the others interact. Consistent with these requirements, we observe that in glucose-grown mig1Δ cells, Nup133 still binds the SUC2 promoter, although the strength of the interaction appears to be reduced (Fig. 2B).

Although interesting, this finding is far from conclusive, and further work must be done to test the accuracy of the idea. If it is correct, classical biochemical theory predicts that adding either individual nucleoporin(s) or intact nuclear pores to in vitro DNA-binding reactions should increase the affinity of Mig1 for its site. However, if in vivo nuclear context is important—perhaps for reducing search time by compressing three dimensions into two – then in vitro analyses such as this may not be informative. In which case, quantitative measurement of in vivo DNA binding at different nuclear locations, either by fluorescent resonance energy transfer (FRET) or bimolecular fluorescence complementation (BiFC), may provide the best test of this model. It will also be critical to definitively address the question of where in the yeast nucleus promoter-nucleoporin interactions truly occur. Circumstantial evidence—the periodic localization of the DNA to the nuclear periphery, together with the relative immobility of the nucleoporins we observe to interact with it—strongly suggests that intact, membrane-embedded NPCs influence Mig1 DNA binding. However, at this time, we cannot rule out a role for soluble nucleoplasmic pools of nucleoporins. Determining whether an interaction occurs in one or the other of two specific locations—the nuclear periphery or the nucleoplasm—may seem straightforward at first. In reality, the need for precise localization in a small nucleus, together with the likelihood that no more than a very few molecules of nucleoporin are localized to the nuclear interior, means that a combination of super-resolution microscopy and single molecule detection techniques will be necessary to answer this question in a satisfactory way.

A second model, not mutually exclusive with the one described above, is that NPCs collaborate with chromatin modifying complexes and chromatin remodelers to fine-tune the post-translational modification and/or position of nucleosomes over many Mig1 target promoters (Fig. 2C). In repressed wild type cells, nucleosomes 1 and 2 of the SUC2 promoter are at least 2- to 5-fold more acetylated than nucleosome 455; 1 and 2 flank the first Mig1 binding site, 2 covers the second Mig1 binding site and 4 covers the TATA box (Fig. 1B). The effect of histone acetylation on Mig1 binding has not been studied directly, but modeling of nucleosome positioning data suggests that these are less stably associated with the DNA in the absence of glucose.56 A change in the targeting or activity of histone acetyltransferases and/or in acetylation-dependent Swi/Snf remodeling, might occur in nup120Δ and nup133Δ mutants, thus altering the position or occupancy of promoter nucleosomes so that binding sites for Mig1 become obscured. In this model, Mig1 cannot repress transcription because it is unable to outcompete these nucleosomes.

Some data exist to support a model in which nucleoporins influence transcriptional regulation by co-operating with chromatin modifying complexes, particularly those that control histone acetylation. This is significant, since acetylation state is believed to be an important determinant of the affinity between nucleosomes and DNA. In Drosophila, the histone acetyltransferase MOF has been found in complex with both Nup153 and the NPC associated protein mTOR.22 Nup153 has also been found to preferentially interact with genomic loci where H4K16Ac-containing nucleosomes are enriched.19 In Saccharomyces, the MOF homolog Esa1, catalytic subunit of NuA4, constitutively associates with the SUC2 promoter.57 Deletion of ESA1 is synthetically defective with deletion of NUP120, suggesting the products of these genes share some common function58; this interesting possibility has not yet been explored. Yeast Gcn5, the catalytic subunit of SAGA, has been shown to associate directly with Mlp1 and 2, homologs of Drosophila mTOR.59 Most recently, the Rattus norvegicus nucleoporin Nup155 has been shown to interact with the histone deacetylase HDAC4 and to regulate the association of specific genomic loci with that nucleoporin.15

An intriguing but currently even less-well elaborated connection may exist between nuclear pores and chromatin remodeling complexes. The RSC complex is essential both for the localization of NPCs to the nuclear envelope and for normal nuclear morphology, leading to the suggestion that RSC might be required for establishing contacts between chromatin and the NPC.60SUC2 is not known to be a target of RSC, but the promoters of other Mig1-regulated genes, including HXK1 and FBP1, are bound at a low level by RSC in glucose-grown cells.61 Again, further work must be done to determine whether changes in the position or acetylation state of promoter nucleosomes are responsible for the failure of Mig1 to bind DNA in nup120Δ and nup133Δ cells.

Relevance to Leukemia: Nucleoporins as Transcription Factors in Human Cells

Genes encoding components of the NPC are the target of chromosomal translocations in several different types of cancer62-66; possibly the best studied of these translocations are found in hematological malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and T-cell acute lymphocytic leukemia (T-ALL).67-69 Different mechanisms have been proposed to explain how nucleoporin fusions contribute to the development of disease. One hypothesis is that interaction of nucleoporin chimeras with endogenous nucleoporins or RNA export factors may contribute to their leukemogenic properties.70-72 Another is that nucleoporins are involved in spindle formation and this function is disrupted in oncogenic fusions, leading to aneuploidy.69 However, in many cases the translocation partner of the nucleoporin is a transcription factor. NUP98-HOXA9, probably the best-characterized of these leukemogenic nucleoporin fusion proteins,73-77 has long been known to have the ability to bind to DNA and interact with components of the basal transcription machinery, leading to aberrant gene expression.14,20,78-82 The recent work described above strongly suggests that nucleoporins play a role in normal transcriptional regulation; it seems likely, then, that conscription of this function is a primary mechanism of oncogenesis.69 This conclusion is supported by studies of the fusion proteins themselves.

Of particular relevance to our work on Mig1 is a recent study linking NUP98 with the transcription factor AES. AES is a homolog of the Mig1-interacting protein Tup1; both AES and Tup1 are Groucho family proteins that act as co-repressors of transcription. Importantly, AES interacts with both wild type NUP98 and NUP98-HOXA9, consistent with the idea of a conserved, nucleoporin-dependent mechanism of transcriptional regulation that is hijacked in leukemogenesis. Together, AES and NUP98-HOXA9 cooperate to regulate transcription, cell transformation and the impairment of hematopoietic differentiation.79,80

Functional and physical links have also been described between NUP98 fusions and chromatin modifiers. The FG repeats in the NUP98 portion of a NUP98-HOXA9 fusion physically interact with CREB-binding protein (CBP)/p300; transcriptional activation of a reporter gene by NUP98-HOXA9 is dependent on the histone acetyltransferase activity of CBP/p300.81 Chromosomal translocations also fuse NUP98 to the lysine methyltransferases NSD1 and MLL, to the lysine demethylase JARID1A and to the poorly-characterized protein PHF23, which recognizes methylated H3K4.69 NUP98-NSD1 promotes the methylation of histone H3-Lys36 (H3K36) at loci encoding several proto-oncogenes, including HoxA7, HoxA9, HoxA10 and Meis1; enforced activation of these transcription factors then blocks differentiation.83 NUP98-JARID1A and NUP98-PHF23 fusion proteins inhibit demethylation of histone H3-Lys 4 (H3K4me3) at loci encoding lineage-specific transcription factors, again blocking differentiation.84,85 It is not clear how the deregulation of lysine methylation by these NUP98 chimeras relates to nucleoporin-mediated regulation of gene expression described above. However, in Drosophila cells, the methylation state of H3K36 is linked to levels of H4K16 acetylation,86,87 and nucleoporins preferentially bind loci enriched for H4K16Ac.19,20

Conclusions and Future Directions

These observations bring up an important question: to what extent is transcriptional regulation by nucleoporins conserved in healthy and cancerous cells? The work summarized above suggests that it is, to at least some extent. Where this is true, with what partner proteins do they work, and how do these differ at different stages of transcript production? How can their contribution be integrated into existing models of gene regulation? Addressing these questions should help us to understand how multiple steps of transcript synthesis are coupled, bringing us closer to a full understanding of how gene expression is regulated in a nuclear context.


Previously published online:


We thank George Santangelo for important theoretical contributions; Dan Larson and Vytas Bankaitis for comments on the manuscript and Patrick Varga-Weisz for comments on the manuscript, as well as for a generous amount of time spent in helpful discussions of the text. This work was supported by National Institutes of Health grant GM083309 to K.A.W.


NPC nuclear pore complex
TBP TATA binding protein
GFP green fluorescent protein
TSS transcription start site
HDAC histone deacetylase

1. Cosma MP. Ordered recruitment: gene-specific mechanism of transcription activationMol CellYear: 2002102273610.1016/S1097-2765(02)00604-412191469
2. Orphanides G,Reinberg D. A unified theory of gene expressionCellYear: 20021084395110.1016/S0092-8674(02)00655-411909516
3. Krishnamurthy S,Hampsey M. Eukaryotic transcription initiationCurr BiolYear: 200919R153610.1016/j.cub.2008.11.05219243687
4. Weake VM,Workman JL. Inducible gene expression: diverse regulatory mechanismsNat Rev GenetYear: 2010114263710.1038/nrg278120421872
5. Hahn S,Young ET. Transcriptional regulation in Saccharomyces cerevisiae: transcription factor regulation and function, mechanisms of initiation, and roles of activators and coactivatorsGeneticsYear: 20111897053610.1534/genetics.111.12701922084422
6. Malik S,Roeder RG. The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulationNat Rev GenetYear: 2010117617210.1038/nrg290120940737
7. Saunders A,Core LJ,Lis JT. Breaking barriers to transcription elongationNat Rev Mol Cell BiolYear: 200675576710.1038/nrm198116936696
8. Bryant GO,Ptashne M. Independent recruitment in vivo by Gal4 of two complexes required for transcriptionMol CellYear: 2003111301910.1016/S1097-2765(03)00144-812769853
9. Carey MF, Peterson CL, Smale ST. Transcriptional Regulation in Eukaryotes: Concepts, Strategies, & Techniques. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2009.
10. Maniatis T,Reed R. An extensive network of coupling among gene expression machinesNatureYear: 200241649950610.1038/416499a11932736
11. Pandit S,Wang D,Fu XD. Functional integration of transcriptional and RNA processing machineriesCurr Opin Cell BiolYear: 200820260510.1016/
12. Proudfoot NJ,Furger A,Dye MJ. Integrating mRNA processing with transcriptionCellYear: 20021085011210.1016/S0092-8674(02)00617-711909521
13. Sarma NJ,Haley TM,Barbara KE,Buford TD,Willis KA,Santangelo GM. Glucose-responsive regulators of gene expression in Saccharomyces cerevisiae function at the nuclear periphery via a reverse recruitment mechanismGeneticsYear: 200717511273510.1534/genetics.106.06893217237508
14. Capelson M,Liang Y,Schulte R,Mair W,Wagner U,Hetzer MW. Chromatin-bound nuclear pore components regulate gene expression in higher eukaryotesCellYear: 20101403728310.1016/j.cell.2009.12.05420144761
15. Kehat I,Accornero F,Aronow BJ,Molkentin JD. Modulation of chromatin position and gene expression by HDAC4 interaction with nucleoporinsJ Cell BiolYear: 201119321910.1083/jcb.20110104621464227
16. Casolari JM,Brown CR,Komili S,West J,Hieronymus H,Silver PA. Genome-wide localization of the nuclear transport machinery couples transcriptional status and nuclear organizationCellYear: 20041174273910.1016/S0092-8674(04)00448-915137937
17. Dilworth DJ,Tackett AJ,Rogers RS,Yi EC,Christmas RH,Smith JJ,et al. The mobile nucleoporin Nup2p and chromatin-bound Prp20p function in endogenous NPC-mediated transcriptional controlJ Cell BiolYear: 20051719556510.1083/jcb.20050906116365162
18. Brown CR,Kennedy CJ,Delmar VA,Forbes DJ,Silver PA. Global histone acetylation induces functional genomic reorganization at mammalian nuclear pore complexesGenes DevYear: 2008226273910.1101/gad.163270818316479
19. Vaquerizas JM,Suyama R,Kind J,Miura K,Luscombe NM,Akhtar A. Nuclear pore proteins nup153 and megator define transcriptionally active regions in the Drosophila genomePLoS GenetYear: 20106e100084610.1371/journal.pgen.100084620174442
20. Kalverda B,Pickersgill H,Shloma VV,Fornerod M. Nucleoporins directly stimulate expression of developmental and cell-cycle genes inside the nucleoplasmCellYear: 20101403607110.1016/j.cell.2010.01.01120144760
21. Finlan LE,Sproul D,Thomson I,Boyle S,Kerr E,Perry P,et al. Recruitment to the nuclear periphery can alter expression of genes in human cellsPLoS GenetYear: 20084e100003910.1371/journal.pgen.100003918369458
22. Mendjan S,Taipale M,Kind J,Holz H,Gebhardt P,Schelder M,et al. Nuclear pore components are involved in the transcriptional regulation of dosage compensation in DrosophilaMol CellYear: 2006218112310.1016/j.molcel.2006.02.00716543150
23. Watson ML. Further observations on the nuclear envelope of the animal cellJ Biophys Biochem CytolYear: 195961475610.1083/jcb.6.2.14713843146
24. Callan HG,Randall JT,Tomlin SG. An electron microscope study of the nuclear membraneNatureYear: 194916328010.1038/163280a018112254
25. Callan HG,Tomlin SG. Experimental studies on amphibian oocyte nuclei. I. Investigation of the structure of the nuclear membrane by means of the electron microscopeProc R Soc Lond B Biol SciYear: 19501373677810.1098/rspb.1950.004714786306
26. Gall JG. Observations on the nuclear membrane with the electron microscopeExp Cell ResYear: 1954719720010.1016/0014-4827(54)90054-313200519
27. Anderson E,Beams HW. Evidence from electron micrographs for the passage of material through pores of the nuclear membraneJ Biophys Biochem CytolYear: 19562Suppl4394410.1083/jcb.2.4.43913357583
28. Beams HW,Tahmisian TN,Anderson E,Devine RL. The structure of nuclear membrane in larval gonads of Heliothis obsoletaProc Soc Exp Biol MedYear: 195691473513322969
29. Aaronson RP,Blobel G. Isolation of nuclear pore complexes in association with a laminaProc Natl Acad Sci U S AYear: 19757210071110.1073/pnas.72.3.10071055359
30. Grünwald D,Singer RH,Rout M. Nuclear export dynamics of RNA-protein complexesNatureYear: 20114753334110.1038/nature1031821776079
31. Hoelz A,Debler EW,Blobel G. The structure of the nuclear pore complexAnnu Rev BiochemYear: 2011806134310.1146/annurev-biochem-060109-15103021495847
32. DuPraw E. Cell and Molecular Biology. New York: Academic Press, 1958:424.
33. Dupraw EJ. Cell and Molecular Biology. NY: Academic Press, 1954.
34. Comings DE,Okada TA. Association of nuclear membrane fragments with metaphase and anaphase chromosomes as observed by whole mount electron microscopyExp Cell ResYear: 19706362810.1016/0014-4827(70)90331-95531486
35. Kirschner RH,Rusli M,Martin TE. Characterization of the nuclear envelope, pore complexes, and dense lamina of mouse liver nuclei by high resolution scanning electron microscopyJ Cell BiolYear: 1977721183210.1083/jcb.72.1.118556616
36. Chan JK,Park PC,De Boni U. Association of DNAse sensitive chromatin domains with the nuclear periphery in 3T3 cells in vitroBiochem Cell BiolYear: 200078677810.1139/o99-07410874467
37. Hutchison N,Weintraub H. Localization of DNAase I-sensitive sequences to specific regions of interphase nucleiCellYear: 1985434718210.1016/0092-8674(85)90177-14075401
38. Markovics J,Glass L,Maul GG. Pore patterns on nuclear membranesExp Cell ResYear: 1974854435110.1016/0014-4827(74)90148-74827878
39. Arlucea J,Andrade R,Alonso R,Aréchaga J. The nuclear basket of the nuclear pore complex is part of a higher-order filamentous network that is related to chromatinJ Struct BiolYear: 199812451810.1006/jsbi.1998.40549931273
40. Light WH,Brickner DG,Brand VR,Brickner JH. Interaction of a DNA zip code with the nuclear pore complex promotes H2A.Z incorporation and INO1 transcriptional memoryMol CellYear: 2010401122510.1016/j.molcel.2010.09.00720932479
41. Schmid M,Arib G,Laemmli C,Nishikawa J,Durussel T,Laemmli UK. Nup-PI: the nucleopore-promoter interaction of genes in yeastMol CellYear: 2006213799110.1016/j.molcel.2005.12.01216455493
42. Griffis ER,Altan N,Lippincott-Schwartz J,Powers MA. Nup98 is a mobile nucleoporin with transcription-dependent dynamicsMol Biol CellYear: 20021312829710.1091/mbc.01-11-053811950939
43. Griffis ER,Craige B,Dimaano C,Ullman KS,Powers MA. Distinct functional domains within nucleoporins Nup153 and Nup98 mediate transcription-dependent mobilityMol Biol CellYear: 2004151991200210.1091/mbc.E03-10-074314718558
44. Dilworth DJ,Suprapto A,Padovan JC,Chait BT,Wozniak RW,Rout MP,et al. Nup2p dynamically associates with the distal regions of the yeast nuclear pore complexJ Cell BiolYear: 200115314657810.1083/jcb.153.7.146511425876
45. Nakielny S,Shaikh S,Burke B,Dreyfuss G. Nup153 is an M9-containing mobile nucleoporin with a novel Ran-binding domainEMBO JYear: 19991819829510.1093/emboj/18.7.198210202161
46. Rabut G,Doye V,Ellenberg J. Mapping the dynamic organization of the nuclear pore complex inside single living cellsNat Cell BiolYear: 2004611142110.1038/ncb118415502822
47. Rasala BA,Orjalo AV,Shen Z,Briggs S,Forbes DJ. ELYS is a dual nucleoporin/kinetochore protein required for nuclear pore assembly and proper cell divisionProc Natl Acad Sci U S AYear: 200610317801610.1073/pnas.060848410317098863
48. Santangelo GM. Glucose signaling in Saccharomyces cerevisiaeMicrobiol Mol Biol RevYear: 2006702538210.1128/MMBR.70.1.253-282.200616524925
49. Cabal GG,Genovesio A,Rodriguez-Navarro S,Zimmer C,Gadal O,Lesne A,et al. SAGA interacting factors confine sub-diffusion of transcribed genes to the nuclear envelopeNatureYear: 2006441770310.1038/nature0475216760982
50. Taddei A,Van Houwe G,Hediger F,Kalck V,Cubizolles F,Schober H,et al. Nuclear pore association confers optimal expression levels for an inducible yeast geneNatureYear: 2006441774810.1038/nature0484516760983
51. Entian KD. Genetic and biochemical evidence for hexokinase PII as a key enzyme involved in carbon catabolite repression in yeastMol Gen GenetYear: 1980178633710.1007/BF003378716993859
52. Neigeborn L,Carlson M. Genes affecting the regulation of SUC2 gene expression by glucose repression in Saccharomyces cerevisiaeGeneticsYear: 1984108845586392017
53. Neigeborn L,Carlson M. Mutations causing constitutive invertase synthesis in yeast: genetic interactions with snf mutationsGeneticsYear: 1987115247533549450
54. Sarma NJ,Buford TD,Haley T,Barbara-Haley K,Santangelo GM,Willis KA. The nuclear pore complex mediates binding of the Mig1 repressor to target promotersPLoS OneYear: 20116e2711710.1371/journal.pone.002711722110603
55. Boukaba A,Georgieva EI,Myers FA,Thorne AW,López-Rodas G,Crane-Robinson C,et al. A short-range gradient of histone H3 acetylation and Tup1p redistribution at the promoter of the Saccharomyces cerevisiae SUC2 geneJ Biol ChemYear: 200427976788410.1074/jbc.M31084920014670975
56. Zawadzki KA,Morozov AV,Broach JR. Chromatin-dependent transcription factor accessibility rather than nucleosome remodeling predominates during global transcriptional restructuring in Saccharomyces cerevisiaeMol Biol CellYear: 20092035031310.1091/mbc.E09-02-011119494041
57. Geng F,Laurent BC. Roles of SWI/SNF and HATs throughout the dynamic transcription of a yeast glucose-repressible geneEMBO JYear: 2004231273710.1038/sj.emboj.760003514685262
58. Mitchell L,Lambert JP,Gerdes M,Al-Madhoun AS,Skerjanc IS,Figeys D,et al. Functional dissection of the NuA4 histone acetyltransferase reveals its role as a genetic hub and that Eaf1 is essential for complex integrityMol Cell BiolYear: 20082822445610.1128/MCB.01653-0718212056
59. Luthra R,Kerr SC,Harreman MT,Apponi LH,Fasken MB,Ramineni S,et al. Actively transcribed GAL genes can be physically linked to the nuclear pore by the SAGA chromatin modifying complexJ Biol ChemYear: 20072823042910.1074/jbc.M60874120017158105
60. Titus LC,Dawson TR,Rexer DJ,Ryan KJ,Wente SR. Members of the RSC chromatin-remodeling complex are required for maintaining proper nuclear envelope structure and pore complex localizationMol Biol CellYear: 20102110728710.1091/mbc.E09-07-061520110349
61. Ng HH,Robert F,Young RA,Struhl K. Genome-wide location and regulated recruitment of the RSC nucleosome-remodeling complexGenes DevYear: 2002168061910.1101/gad.97890211937489
62. Gould VE,Orucevic A,Zentgraf H,Gattuso P,Martinez N,Alonso A. Nup88 (karyoporin) in human malignant neoplasms and dysplasias: correlations of immunostaining of tissue sections, cytologic smears, and immunoblot analysisHum PatholYear: 2002335364410.1053/hupa.2002.12478512094380
63. Graux C,Cools J,Melotte C,Quentmeier H,Ferrando A,Levine R,et al. Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemiaNat GenetYear: 2004361084910.1038/ng142515361874
64. Soman NR,Wogan GN,Rhim JS. TPR-MET oncogenic rearrangement: detection by polymerase chain reaction amplification of the transcript and expression in human tumor cell linesProc Natl Acad Sci U S AYear: 1990877384210.1073/pnas.87.2.7382300559
65. Ma Z,Hill DA,Collins MH,Morris SW,Sumegi J,Zhou M,et al. Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumorGenes Chromosomes CancerYear: 2003379810510.1002/gcc.1017712661011
66. Köhler A,Hurt E. Gene regulation by nucleoporins and links to cancerMol CellYear: 20103861510.1016/j.molcel.2010.01.04020385085
67. Xu S,Powers MA. Nuclear pore proteins and cancerSemin Cell Dev BiolYear: 2009206203010.1016/j.semcdb.2009.03.00319577736
68. Lam DH,Aplan PD. NUP98 gene fusions in hematologic malignanciesLeukemiaYear: 20011516899510.1038/sj.leu.240226911681408
69. Gough SM,Slape CI,Aplan PD. NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insightsBloodYear: 201111862475710.1182/blood-2011-07-32888021948299
70. Funasaka T,Nakano H,Wu Y,Hashizume C,Gu L,Nakamura T,et al. RNA export factor RAE1 contributes to NUP98-HOXA9-mediated leukemogenesisCell CycleYear: 20111014566710.4161/cc.10.9.1549421467841
71. Ren Y,Seo HS,Blobel G,Hoelz A. Structural and functional analysis of the interaction between the nucleoporin Nup98 and the mRNA export factor Rae1Proc Natl Acad Sci U S AYear: 2010107104061110.1073/pnas.100538910720498086
72. Takeda A,Sarma NJ,Abdul-Nabi AM,Yaseen NR. Inhibition of CRM1-mediated nuclear export of transcription factors by leukemogenic NUP98 fusion proteinsJ Biol ChemYear: 2010285162485710.1074/jbc.M109.04878520233715
73. Nakamura T,Largaespada DA,Lee MP,Johnson LA,Ohyashiki K,Toyama K,et al. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemiaNat GenetYear: 199612154810.1038/ng0296-1548563753
74. Raza-Egilmez SZ,Jani-Sait SN,Grossi M,Higgins MJ,Shows TB,Aplan PD. NUP98-HOXD13 gene fusion in therapy-related acute myelogenous leukemiaCancer ResYear: 1998584269739766650
75. Nakamura T,Yamazaki Y,Hatano Y,Miura I. NUP98 is fused to PMX1 homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15)BloodYear: 199994741710397741
76. Panagopoulos I,Isaksson M,Billström R,Strömbeck B,Mitelman F,Johansson B. Fusion of the NUP98 gene and the homeobox gene HOXC13 in acute myeloid leukemia with t(11;12)(p15;q13)Genes Chromosomes CancerYear: 2003361071210.1002/gcc.1013912461755
77. Jankovic D,Gorello P,Liu T,Ehret S,La Starza R,Desjobert C,et al. Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemiaBloodYear: 200811156728210.1182/blood-2007-09-10817518388181
78. Ghannam G,Takeda A,Camarata T,Moore MA,Viale A,Yaseen NR. The oncogene Nup98-HOXA9 induces gene transcription in myeloid cellsJ Biol ChemYear: 20042798667510.1074/jbc.M30728020014561764
79. Yassin ER,Sarma NJ,Abdul-Nabi AM,Dombrowski J,Han Y,Takeda A,et al. Dissection of the transformation of primary human hematopoietic cells by the oncogene NUP98-HOXA9PLoS OneYear: 20094e671910.1371/journal.pone.000671919696924
80. Sarma NJ,Yaseen NR. Amino-terminal enhancer of split (AES) interacts with the oncoprotein NUP98-HOXA9 and enhances its transforming abilityJ Biol ChemYear: 201128638989900110.1074/jbc.M111.29795221937451
81. Kasper LH,Brindle PK,Schnabel CA,Pritchard CE,Cleary ML,van Deursen JM. CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicityMol Cell BiolYear: 199919764769858599
82. Menon BB,Sarma NJ,Pasula S,Deminoff SJ,Willis KA,Barbara KE,et al. Reverse recruitment: the Nup84 nuclear pore subcomplex mediates Rap1/Gcr1/Gcr2 transcriptional activationProc Natl Acad Sci U S AYear: 200510257495410.1073/pnas.050176810215817685
83. Wang GG,Cai L,Pasillas MP,Kamps MP. NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesisNat Cell BiolYear: 200798041210.1038/ncb160817589499
84. Wang GG,Song J,Wang Z,Dormann HL,Casadio F,Li H,et al. Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD fingerNatureYear: 20094598475110.1038/nature0803619430464
85. Reader JC,Meekins JS,Gojo I,Ning Y. A novel NUP98-PHF23 fusion resulting from a cryptic translocation t(11;17)(p15;p13) in acute myeloid leukemiaLeukemiaYear: 200721842417287853
86. Wu SF,Zhang H,Cairns BR. Genes for embryo development are packaged in blocks of multivalent chromatin in zebrafish spermGenome ResYear: 2011215788910.1101/gr.113167.11021383318
87. Bell O,Wirbelauer C,Hild M,Scharf AN,Schwaiger M,MacAlpine DM,et al. Localized H3K36 methylation states define histone H4K16 acetylation during transcriptional elongation in DrosophilaEMBO JYear: 20072649748410.1038/sj.emboj.760192618007591
88. Lundin M,Nehlin JO,Ronne H. Importance of a flanking AT-rich region in target site recognition by the GC box-binding zinc finger protein MIG1Mol Cell BiolYear: 1994141979858114729
89. Pérez-Ortín JE,Estruch F,Matallana E,Franco L. Fine analysis of the chromatin structure of the yeast SUC2 gene and of its changes upon derepression. Comparison between the chromosomal and plasmid-inserted genesNucleic Acids ResYear: 19871569375610.1093/nar/15.17.69372821486
90. Wu L,Winston F. Evidence that Snf-Swi controls chromatin structure over both the TATA and UAS regions of the SUC2 promoter in Saccharomyces cerevisiaeNucleic Acids ResYear: 1997254230410.1093/nar/25.21.42309336451
91. Gavin IM,Simpson RT. Interplay of yeast global transcriptional regulators Ssn6p-Tup1p and Swi-Snf and their effect on chromatin structureEMBO JYear: 19971662637110.1093/emboj/16.20.62639321405
92. Hirschhorn JN,Bortvin AL,Ricupero-Hovasse SL,Winston F. A new class of histone H2A mutations in Saccharomyces cerevisiae causes specific transcriptional defects in vivoMol Cell BiolYear: 199515199920097891695
93. Hirschhorn JN,Brown SA,Clark CD,Winston F. Evidence that SNF2/SWI2 and SNF5 activate transcription in yeast by altering chromatin structureGenes DevYear: 1992612A22889810.1101/gad.6.12a.22881459453
94. Schwabish MA,Struhl K. The Swi/Snf complex is important for histone eviction during transcriptional activation and RNA polymerase II elongation in vivoMol Cell BiolYear: 20072769879510.1128/MCB.00717-0717709398
95. Dror V,Winston F. The Swi/Snf chromatin remodeling complex is required for ribosomal DNA and telomeric silencing in Saccharomyces cerevisiaeMol Cell BiolYear: 20042482273510.1128/MCB.24.18.8227-8235.200415340082
96. Fleming AB,Pennings S. Tup1-Ssn6 and Swi-Snf remodelling activities influence long-range chromatin organization upstream of the yeast SUC2 geneNucleic Acids ResYear: 20073555203110.1093/nar/gkm57317704134
97. Pollard KJ,Peterson CL. Role for ADA/GCN5 products in antagonizing chromatin-mediated transcriptional repressionMol Cell BiolYear: 1997176212229343382
98. Sudarsanam P,Cao Y,Wu L,Laurent BC,Winston F. The nucleosome remodeling complex, Snf/Swi, is required for the maintenance of transcription in vivo and is partially redundant with the histone acetyltransferase, Gcn5EMBO JYear: 1999183101610.1093/emboj/18.11.310110357821
99. Neigeborn L,Celenza JL,Carlson M. SSN20 is an essential gene with mutant alleles that suppress defects in SUC2 transcription in Saccharomyces cerevisiaeMol Cell BiolYear: 1987767283547080
100. Adkins MW,Tyler JK. Transcriptional activators are dispensable for transcription in the absence of Spt6-mediated chromatin reassembly of promoter regionsMol CellYear: 2006214051610.1016/j.molcel.2005.12.01016455495
101. Türkel S,Turgut T,López MC,Uemura H,Baker HV. Mutations in GCR1 affect SUC2 gene expression in Saccharomyces cerevisiaeMol Genet GenomicsYear: 20032688253112655409
102. Sasaki H,Uemura H. Influence of low glycolytic activities in gcr1 and gcr2 mutants on the expression of other metabolic pathway genes in Saccharomyces cerevisiaeYeastYear: 2005221112710.1002/yea.119815645478
103. Barbara KE,Haley TM,Willis KA,Santangelo GM. The transcription factor Gcr1 stimulates cell growth by participating in nutrient-responsive gene expression on a global levelMol Genet GenomicsYear: 20072771718810.1007/s00438-006-0182-017124610
104. López MC,Baker HV. Understanding the growth phenotype of the yeast gcr1 mutant in terms of global genomic expression patternsJ BacteriolYear: 20001824970810.1128/JB.182.17.4970-4978.200010940042


[Figure ID: F1]

Figure 1. Regulation of glucose-repressed gene expression in Saccharomyces cerevisiae. Regulation of SUC2 expression is well characterized, and the proteins that carry out this regulation have been studied extensively. The SUC2 system therefore provides a good model for understanding how other genes controlled by the same factors are regulated. (A) A kinase-transcription factor pair work together to control expression of SUC2. Left panel. In the presence of glucose (repressed), the C2H2 zinc finger protein Mig1 binds DNA and inhibits transcription of SUC2, plus approximately 300 other genes. Complete inhibition also requires the hexokinase Hxk2. Snf1 kinase, a structural and functional homolog of mammalian AMPK, is found in the cytoplasm. Right panel. When glucose is depleted or withdrawn (derepressed), Snf1 is phosphorylated by upstream kinases, enters the nucleus and phosphorylates Mig1, which is then exported together with Hxk2. For detailed review, see reference 48. (B) Chromatin structure of the SUC2 promoter. Left panel. In the presence of glucose (repressed), four nucleosomes (numbered 1 through 4) cover the SUC2 promoter; a gradient of histone H3 acetylation decreases from 5′ to 3′.55 Two GC-rich sequences are required for repression of transcription (red t-bars) from the TSS (dashed black arrow).88 These sites are interchangeably bound in vivo by Mig1 and its homolog Mig2; function of the former, but not the latter, is regulated by the Snf1 kinase.48 The average location of the first Mig1/2 site (left-most red rectangle) is between nucleosomes 1 and 2. The second Mig1/2 site (right-most red rectangle) is close to the end of the DNA covered by nucleosome 289-91; nucleosome and repressor may compete for occupancy of this site. The TATA box (green rectangle) is covered by nucleosome 4.89-93 Right panel. Full induction of transcription requires the Swi/Snf chromatin remodeling complex.57,90,91,94-98 Swi/Snf associates more stably with promoter nucleosomes that have been acetylated by SAGA and NuA4 complexes57; in the absence of glucose, acetylation of H3 and H4 tails increases for all nucleosomes. The DNA formerly covered by two nucleosomes (nucleosomes 2 and 3) is more frequently covered by only one. Nucleosome 4, covering the TATA box, is hyperacetlyated and becomes unstable.55 Initiation occurs at the TSS (black arrow). Additionally required for full induction of SUC2 transcription are the nucleosome remodeling protein Spt699,100 and the transcriptional activator Gcr1 (blue oval, Gcr1 binding site).90,101-104 Nuclear pore proteins also interact with the SUC2 promoter13; it is important to learn how they collaborate with the well-characterized transcription factors described here.

[Figure ID: F2]

Figure 2. How nucleoporins might influence access to a specific site in DNA. (A) Model for NPC facilitated Mig1 binding to DNA. (a) In the presence of glucose, Mig1 associates with NPCs; the SUC2 locus contacts NPCs transiently. (b) Increased local concentration of both Mig1 and its consensus site facilitates DNA binding by the repressor. (c) The repressor-bound promoter can dissociate from the NPC. (B) Interaction of Nup133 with the SUC2 promoter is reduced in mig1Δ cells. TAP-tagged Nup133 was immunoprecipitated from mig1Δ or wild type cells grown in media containing glucose as the carbon source, then fixed with formaldehyde as described previously.13 Crosslinks were reversed and PCR was used to amplify the promoters of SUC2 and ACT1 (negative control) from recovered material. Amplified target is expressed as a ratio of SUC2/ACT1, normalized to the amount of product amplified whole cell extracts (input). Adding increasing amounts of input DNA shows that amplification of the product is linear. A representative experiment is shown; similar results were obtained for Nup145C (not shown). (C) A model for collaborative nucleosome positioning. Top panel. Mig1 associates with nuclear pores as in (A) above. SUC2 is not associated with nuclear pores, and the nucleosomes across its promoter are poorly positioned (three yellow circles, one distinct and two indistinct, represent the average position of one nucleosome, over time and across a population). Bottom panel. One or more subunits of the nuclear pore associate with the SUC2 locus, serving as a marker or barrier against which chromatin remodelers can position a single nucleosome, thus seeding an ordered array. Alternatively, nuclear pore proteins may direct the activity of chromatin modifiers such as SAGA and NuA4, which in turn direct the activity of remodelers such as Swi/Snf. Models shown in A and C are not mutually exclusive; for example, nuclear pores contribute to nucleosome positioning at step (b) of model A.

[TableWrap ID: T1] Table 1. Nuclear pore proteins in physical interaction with genomic loci
  Nucleoporin Yeast homolog References
16, 17, 41
13, 16
19, 22
14, 20
Active and
Homo sapiens
Active and repressed Nup93 Nic96 18

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Keywords: Keywords: AMPK, NPC, Nup120, Nup133, RNA polymerase II, acute myeloid leukemia, glucose, glucose metabolism, glucose-regulated gene expression, nuclear pore complex, transcriptional regulation.

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