Gating Pluripotency Via Nuclear Pores

Opinion

Gating pluripotency via nuclear pores

1* 1* 2* 1,3,4 1

Jiping Yang , Ning Cai , Fei Yi , Guang-Hui Liu , Jing Qu , and

2,5

Juan Carlos Izpisua Belmonte

National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China

Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

Beijing Institute for Brain Disorders, Beijing, China

Center for Regenerative Medicine in Barcelona, Dr. Aiguader 88, 08003 Barcelona, Spain

In recent years, growing evidence has pointed to the inﬂuence their nuclear trafﬁcking through nuclear pores

interesting idea that pluripotency might be regulated by and subsequently regulate cell-fate determination.

a nuclear-pore-coordinated network that controls the

level of pluripotency factors in the nucleus. A thorough Oct4

understanding of this process might improve our com- Lin et al. reported that the phosphorylation of Oct4 at T235

prehension of cell pluripotency and differentiation dur- by an Akt protein kinase promoted self-renewal and surviv-

ing embryogenesis, as well as aiding the development of al of embryonal carcinoma cells (ECCs) — the malignant

novel models for studying human diseases. counterpart of ESCs [2]. Akt-mediated phosphorylation

prevented Oct4 from being degraded and increased the

Introduction stability of intracellular Oct4. Stabilized Oct4 exhibited

Nuclear-pore complexes (NPCs) are multi-protein chan- predominant nuclear localization (Figure 1). However,

nels that are embedded in the nuclear envelope and are when cells were treated with MG132, a proteasome inhibi-

comprised of approximately 30 different nucleoporins tor, the Oct4-T235A mutant, which cannot be phosphory-

(Nups). NPCs serve as the primary conduit for communi- lated by Akt, accumulated more in the cytoplasm as

cation between the nucleus and cytoplasm. Nucleocyto- compared to wild-type Oct4 or the Oct4-T235D phosphory-

plasmic trafﬁcking via NPCs is a complex yet precise lation mimic. These observations indicate that unpho-

mechanism that is mediated by many transport factors, sphorylated Oct4 is exported from the nucleus and

such as importins, exportins, the GTP-binding nuclear degraded in the cytoplasm. Importantly, treatment with a

protein Ran, and Nups (Box 1). In addition to their primary speciﬁc Akt inhibitor, Akti-1/2, together with MG132

function in nucleocytoplasmic trafﬁcking, nuclear pores markedly accelerated the cytoplasmic accumulation of

are involved in a number of important cellular processes, Oct4, a phenomenon that could be partially reversed by

including gene regulation and chromatin organization [1]. the nuclear export inhibitor leptomycin B (LMB) [2]. There-

Recently, an emerging role of nuclear pores in regulating fore, Akt-mediated phosphorylation stabilizes Oct4 in the

pluripotency and differentiation has been revealed [2–7]. nucleus and prevents it from being exported from the nu-

cleus via nuclear pores, a mechanism that presumably

Regulating nuclear transport of pluripotency factors via involves the export factor CRM1 (also known as exportin-

post-translational modiﬁcations 1). Although most of the previous evidence suggests that the

Pluripotency factors such as POU class 5 homeobox 1 nuclear export of Oct4 is an active process that is regulated

(POU5F1, also known as Oct4), SRY(sex determining by CRM1, a recent study proposed an alternative model,

region Y)-box 2 (Sox2), and Nanog homeobox (Nanog) claiming that most Oct4 is exported from the nucleus by

are transcription factors that are required for the mainte- passive diffusion [8]. Despite the possible controversy, it

nance of pluripotency and suppression of lineage-speciﬁc remains to be elucidated how different mechanisms coordi-

differentiation in pluripotent stem cells (PSCs), including nately regulate nuclear export of Oct4. In addition, it has

embryonic stem cells (ESCs). In order to perform their been suggested that Oct4 requires Akt-mediated phosphor-

functions, these factors need to access the nucleus, which is ylation to maintain the association with other pluripotency

gated by nuclear pores. Recent studies have shown that factors, such as Sox2 and Kruppel-like factor 4 (KLF4) [2].

post-translational modiﬁcations of pluripotency factors By regulating the binding afﬁnity of Oct4 to Sox2 at gene

promoters, Akt-mediated phosphorylation might directly

Corresponding authors: Liu, G.-H. ([email protected]); Qu, J. ([email protected]); increase the transcription of other pluripotency genes, such

Belmonte, J.C.I. ([email protected], [email protected]). as Nanog [2]. Thus, Akt-mediated phosphorylation causes

These authors contributed equally to this work.

both nuclear accumulation of Oct4 and increased Oct4

1471-4914/$ – see front matter

transcriptional activity by promoting its partnering with

Sox2, and together these processes contribute to the self-

renewal and survival of ECCs [2].

The phosphorylation of Oct4 at different sites might

also determine its nucleocytoplasmic redistribution or

Trends in Molecular Medicine, January 2014, Vol. 20, No. 1 1

Opinion Trends in Molecular Medicine January 2014, Vol. 20, No. 1

Box 1. Nucleocytoplasmic trafficking mechanism showed that serine 105 of Oct4 was a putative phosphor-

ylation site for casein kinase II (CK-II), which has been

Nucleocytoplasmic trafficking via nuclear-pore complexes (NPCs)

previously proven to have a central role in facilitating

includes energy-independent passive diffusion and energy-depen-

dent active transport. Small molecules undergo passive diffusion to phosphorylation of nuclear proteins and mediating their

enter the nucleus without regulation and use of energy. However, nucleocytoplasmic shuttling via a CRM1-dependent

macromolecules, such as most transcription factors, histones,

mechanism (Figure 1). More recently, the same group

mRNA, or non-coding RNAs, are actively transported, and these

demonstrated that Oct4 was phosphorylated at serine

processes are mediated by transport factors, such as importins,

111 by the Mitogen-activated protein kinase kinase/ Ex-

exportins, the GTP-binding nuclear protein Ran, and nucleoporins.

Importins are the most important participants in nuclear importing. tracellular signal-regulated kinases 1 (also known as

These proteins are able to recognize the specific amino acid

MEK/ERK1) signaling pathway. Instead of increasing

sequences — nuclear localization signals (NLSs) — on cargos.

the nuclear localization and stabilizing the protein, this

Importins, which bind cargos in the cytoplasm, interact with NPCs to

site-speciﬁc phosphorylation of Oct4 triggered its CRM1-

get through the channel. As long as the cargos enter the nucleus,

importins disassociate from the cargos and return to the cytoplasm. mediated nuclear export and ubiquitin-proteasomal deg-

Importin-a and importin-b are the best-known importins and have radation [9] (Figure 1). Although the essential role of Oct4

been shown to import many proteins, such as POU class 5

in governing pluripotency is well established, a recent

homeobox 1 (POU5F1, also known as Oct4) and SRY(sex determin-

study has uncovered differential roles for Oct4 in main-

ing region Y)-box 2 (Sox2). Conversely, exportins bind to the nuclear

taining or reconstructing pluripotency through Oct4

export signals (NESs) of cargos and exit from the nucleus through

the pores to the cytoplasm, where the exportin–cargo complexes nucleocytoplasmic shuttling. Data demonstrated that

disassemble. The export factor CRM1, also known as exportin-1, transient retention of Oct4 in the nucleus was sufﬁcient

exports cargos with leucine-rich NESs; exportin-5 specifically

to maintain an undifferentiated state in ESCs, whereas

mediates the exit of microRNA. Ran proteins are responsible for

the long-term intranuclear localization of Oct4 was critical

the supply of energy. Ran hydrolyzes GTP to GDP and produces

for cell reprogramming-associated chromatin remodeling

energy for nuclear transport. Nucleocytoplasmic trafficking pre-

cisely controls the localization of macromolecules, which in turn and epigenetic modiﬁcations [8]. This ﬁnding revealed an

might regulate processes related to cell pluripotency and differ- underappreciated role of Oct4 nucleocytoplasmic shut-

entiation.

tling in cell-fate determination. However, the underlying

mechanism remains to be elucidated.

degradation. Ferro et al. showed that Oct4 was phosphor-

ylated at serines 105 and 107 and became mainly cyto- Sox2

plasmic after the differentiation of dental pulp stem cells Another pluripotency factor, Sox2, has also been proposed

(DPSCs) into osteoblastic, hepatic, myocytic, and neural to be governed by nuclear-pore-mediated regulation, which

lineages. Conversely, Oct4 was localized not only in the might affect cell-fate determination. For example, protein

cytoplasm but also in the nucleus in undifferentiated acetylation had been identiﬁed to have a direct effect on

DPSCs [3]. Furthermore, phosphorylation-motif analysis nuclear transport of Sox2 [10]. Sox2 had been shown to

Degradaon of Oct4 and Sox2

Cytoplasm

Nucleus

CRM1 ? CRM1 ?

Pluripotency Sox2 Oct4 Oct4 factors Oct4 P P Ace Oct4 P AKT Promoter

MEK/ERK1 CK-II p300/CBP

TRENDS in Molecular Medicine

Figure 1. Regulation of nuclear localization and function of POU class 5 homeobox 1 (POU5F1, also known as Oct4) and SRY(sex determining region Y)-box 2 (Sox2) via

post-translational modifications. Phosphorylation mediated by Mitogen-activated protein kinase kinase/extracellular signal-regulated kinases 1 (MEK/ERK1) or casein

kinase-II (CK-II) leads to the nuclear export and degradation of Oct4, thereby triggering cell differentiation. The transcriptional coactivators p300/CBP-mediated acetylation

results in the nuclear export and subsequent degradation of Sox2 in the cytoplasm. Finally, Akt-dependent phosphorylation of Oct4 prevents its nuclear export, resulting in

the transcriptional induction of pluripotency genes.

Opinion Trends in Molecular Medicine January 2014, Vol. 20, No. 1

translocate from the cytoplasm into the nucleus during the These studies indicate that nuclear localization of plur-

early stages of embryogenesis, indicating that subcellular ipotency factors is critical for the maintenance of ESCs and

shuttling might be important for its activity [10]. Baltus serves as a molecular switch for cell differentiation.

et al. discovered that CREB-binding protein (CBP)/p300

acetylated lysine 75 on the nuclear export signal (NES) of Importins and exportins

Sox2, which mediated the nuclear export and subsequent The trafﬁcking of pluripotency factors through nuclear

proteasomal degradation of Sox2 in the cytoplasm pores is mediated by different importins and exportins,

(Figure 1). which recognize cargos by speciﬁc NLS or NES sequences.

Importin-a1 has been proven to interact with Oct4 and

Other pluripotency-related factors mediate its nuclear localization. Sox2 has also been

The link between post-translational modiﬁcations and reported to import into the nucleus by three parallel path-

nucleocytoplasmic trafﬁcking has been well studied for ways, through exportin-4, importin-9, or importin-b/7 het-

Oct4 and Sox2 owing to their importance in maintaining erodimer in mouse ESCs [15]. Interestingly, Yasuhara

pluripotency. However, the regulated nucleocytoplasmic et al. found that the expression of different subtypes of

transport of many other pluripotency-related factors — such importin-a changed the nuclear import of a speciﬁc set of

as Klf4 and cMyc, as well as the downstream targets transcription factors, including Oct4, Sox2 and Brn2, a

of Oct4 and Sox2, which are also involved in somatic cell neural lineage-speciﬁc transcription factor, during neural

reprogramming — has not yet been studied to the same differentiation of mouse ESCs [4]. Expression of importin-

depth. In addition, the nuclear transport of histones and a1 was high in undifferentiated ESCs but shut down

basal transcriptional machinery is seldom reported in the rapidly during induced neural differentiation, whereas

context of pluripotency regulation. Therefore, many gaps expression of importin-a3 and importin-a5 gradually in-

in our knowledge remain to be ﬁlled before we have a creased to high levels in differentiated cells. Based on

comprehensive understanding of how nuclear pores further investigations using in vitro nuclear-transport

regulate pluripotency through post-translational modiﬁca- assays, they proposed that in undifferentiated ESCs,

tions of transcription factors. Oct4 is imported into the nucleus by importin-a1/b, where-

as Sox2 is imported by importin-b alone (Figure 2). When

Mechanisms of nuclear transport neural differentiation occurs, downregulation of importin-

Nuclear localization signal, nuclear export signal, and a1 and upregulation of importin-a3/5 are coordinated with

nuclear localization increased nuclear import of Sox2 and a decreased import of

As mentioned above, the NES and nuclear localization Oct4 to initiate differentiation of ESCs. Meanwhile, Brn2

signal (NLS) sequences within transcription factors are is imported into the nucleus in an importin-a5/b-depen-

critical for the nuclear transport machinery and their dent manner, leading to directed neural differentiation

nuclear localization. So far, many groups have identiﬁed (Figure 2). Although importin-a5 seems to be essential

NESs or NLSs within Oct4, Sox2, and Nanog. The presence for the neural differentiation of mouse ESCs, a report

of both NES and NLS sequences in pluripotency factors showed that importin-a5-null mice had normal brain de-

suggests that dynamic nuclear transport might constitute velopment [16]. Moreover, a signiﬁcant upregulation of

a new layer of regulation in pluripotency maintenance and importin-a4 was detected in the brain of importin-a5-null

cell differentiation. For example, Oct4 has been found to mice. Thus, it is likely that importin-a4 could compensate

have a classic NLS localized at amino acid residues 195– for the loss of importin-a5 to ensure normal differentiation.

199 within the N-terminal portion of the homeobox domain Furthermore, Young et al. demonstrated that importin-a2-

(HD) [11]. Mutations in this region prohibited the protein mediated Oct4 nuclear import directly maintained the

from entering the nucleus via nuclear pores and thus pluripotency of mouse ESCs. However, given that impor-

induced the differentiation of P19 cells (mouse ECCs) into tin-a4 was upregulated in differentiated ESCs and over-

trophoblast-like giant cells. expression of importin-a4 could dramatically decrease the

Sox2 has also been reported to contain a leucine-rich Oct4 protein levels, it is clear that importin-a2 and impor-

NES and two functional NLSs within the high mobility tin-a4 have contradictory roles in determining the cell fate

group (HMG) domain [12]. Li et al. demonstrated that of ESCs [17]. Perez-Terzic et al. also discovered that during

mutations within these two NLSs of Sox2 induced the the differentiation of mouse ESCs into cardiomyocytes, the

differentiation of ESCs into the trophectoderm lineage. expression of nuclear transport factors, including impor-

In addition, one putative NES and two NLSs have been tins, exportins, transportins, nucleoporins, and Ran-relat-

identiﬁed in Nanog. Do et al. revealed that the HD of Nanog ed factors, was downregulated globally, whereas the

is essential for its nuclear localization, and they further expression of transportin-2 and Ran-binding protein 6

validated two basic NLSs within the N terminus and C was upregulated [18]. These changes were proposed to

terminus of the HD [13]. Moreover, the same group also correlate with the nuclear entry of cardiac transcription

identiﬁed a putative NES within the HD in which muta- factors such as myocyte enhancer factor 2C (Mef2C), NK2

tions prevented Nanog from exporting [14]. The treatment homeobox 5 (Nkx2.5), and GATA binding protein 4 (Gata4).

of the CRM1-speciﬁc nuclear export inhibitor LMB blocked Additionally, exportin-5 participates in precursor micro-

the export of Nanog, suggesting that the export of Nanog RNA (pre-miRNA) translocation during miRNA matura-

might be mediated by the recognition of CRM1 and NES. tion [19]. Some miRNAs have been linked to key regulators

Nevertheless, the impact of NES mutations on PSCs has of stem cells. For example, miR-21 targets the pluripotency

not yet been speciﬁcally discussed. factors Nanog and Sox2, and thus speciﬁcally suppresses

Opinion Trends in Molecular Medicine January 2014, Vol. 20, No. 1

Neural lineage diﬀerenaon

Imporn- Imporn- Sox2 Imporn-β α5 α Brn2 Oct4 1,2 Imporn- Imporn-β Sox2 α3,5

Cytoplasm Cytoplasm

Nucleus Nucleus

Pluripotency genes Neural genes Oct4 Sox2 Brn2 Sox2 Promoter Promoter

TRENDS in Molecular Medicine

Figure 2. Coordinated nuclear transport of pluripotency and differentiation factors during neural differentiation. Importin-a1 and importin-a2 mediate the nuclear import of

the pluripotency factor POU class 5 homeobox 1 (POU5F1, also known as Oct4) in undifferentiated cells. Upon neural differentiation, importin-a1 and importin-a2 are

repressed, and as a result Oct4 is excluded from the nucleus. Meanwhile, nuclear import of SRY(sex determining region Y)-box 2 (Sox2) by importin-a3 and importin-a5/b is

enhanced, and differentiation factors such as the neural lineage-specific transcription factor Brn2 translocate into the nucleus to activate the downstream targets together

with Sox2.

the self-renewal of ESCs [19]. Importantly, the maturation lineages. Furthermore, they even demonstrated that the

of miRNAs depends on exporting pre-miRNA from the loss of a single Nup133 allele affected the efﬁcient develop-

nucleoplasm into the cytoplasm. Knocking down expor- ment of ESCs into neurons. These observations clearly

tin-5 blocked the export of pre-miRNA 30 [20], whereas indicate that nuclear-pore components might be critical

overexpression of exportin-5 enhanced RNA interference for cell differentiation.

mediated by miRNAs [21]. It is suggested that exportin-5

might somehow be able to regulate pluripotency factors Nup210

indirectly by controlling certain miRNAs. Besides expor- D’Angelo et al. demonstrated that Nup210 is another NPC

tin-5, it is unclear whether there are any other speciﬁc component that is critical for the differentiation of ESCs

exportins that mediate the transportation of miRNA. All towards speciﬁc lineages [5]. They showed that the expres-

these observations suggest that importins and exportins sion of Nup210 was absent in ESCs but increased during

act as important regulators of pluripotency and cell differ- myogenesis or neural differentiation (Figure 3). Knock-

entiation by controlling key factors either directly or down of Nup210 blocked neural differentiation but had

indirectly. no effect on ESC survival, whereas overexpression of

Taken together, it is conceivable that a nuclear-pore- Nup210 accelerated the differentiation process. Interest-

dependent protein-shuttling mechanism is controlling the ingly, even though Nup210 is an important transmem-

nuclear levels of crucial transcription factors involved in brane protein, deﬁciency in Nup210 did not compromise

pluripotency maintenance and differentiation in a precise- nucleocytoplasmic transport, but it did contribute to the

ly tuned manner. dysregulated expression of several differentiation-associ-

ated genes. These observations further suggested a role of

Nuclear-pore components nuclear-pore components in regulating ESC functions [5].

Nup133

The involvement of individual Nups in regulating pluripo- Nup98

tency and differentiation is another aspect that needs to be Nup98, which acts as a docking-site Nup in nucleocyto-

discussed. Certain studies have shown that several nucle- plasmic trafﬁcking, was recently found to be important for

ar-pore components exhibit cell-type-speciﬁc expression human ESC differentiation [7]. Through a genome-wide

and that NPC compositions vary between stem cells and binding analysis, Hetzer et al. identiﬁed a cluster of

differentiated cells. Lupu et al. found that the pluripotency Nup98-bound genes that correlate with differentiation,

of mouse ESCs was regulated by changes in peripheral especially of the neural lineage. Overexpression of a domi-

NPC composition [6] (Figure 3). They showed that the nant negative form of Nup98 repressed the expression of

depletion of Nup133 in mouse ESCs caused an abnormal these Nup98-binding genes, which further conﬁrmed the

pluripotent state and disrupted differentiation into neural activation of such genes through Nup98 binding during

Opinion Trends in Molecular Medicine January 2014, Vol. 20, No. 1

Neural lineage diﬀerenaon

Cytoplasm

Nucleus

Transmembrane ring Transmembrane ring without Nup210 with Nup210

Outer ring Outer ring without Nup133 with Nup133

TRENDS in Molecular Medicine

Figure 3. Changes in nuclear-pore components during neural differentiation. The transmembrane nucleoporin Nup210 and the outer-ring nucleoporin Nup133 are absent in

embryonic stem cells and become expressed during neural differentiation. Both proteins are required for neural lineage commitment.

differentiation [7]. Considering that Nup98 is a mobile Nup stages of differentiation [7]. At the initial stage, the inter-

with the capability of shuttling on and off nuclear pores, actions between Nup98 and chromatin occur in the NPC

the authors proposed that Nup98–gene interactions are periphery for stable microenvironment with the aid of NPC

dynamic and might have diverse patterns during different structures, whereas for genes activated in later stages of

(A) NPCs and pluripotency (B) NPCs and human disorders (C) NPCs and ageing

ESCs iPSCs ANE Nup358 IBSN Nup62 Post-mitoc cells AAAS Aladin (e.g., neurons) AF Nup155

Ageing ? Paents Nuclear + Oct4 + Intranuclear Clinical export Diﬀerenaon Oct4 applicaons Cytoplasm Nup133 + + Lamin A Nucleus Nup210 + ? Certain Reprogramming Imporn-α1 + Nups Paent-derived somac cells ? Imporns Imporn-α3,5 + exporns Reprogramming Normal Increased Drug screening nuclear permeability nuclear permeability Targeted gene correcon and cell therapy Somac cells iPSCs Mechanisc study Young NPCs Old NPCs

TRENDS in Molecular Medicine

Figure 4. Perspectives of nuclear-pore complexes (NPCs) in regulating cell pluripotency (A), as well as mediating human genetic disorders (B) and ageing (C). (A) Increased

nuclear POU class 5 homeobox 1 (POU5F1, also known as Oct4) contributes to a pluripotent stem cell (PSC) identity. Nucleoporin 133 (Nup133) and Nup210 positively

regulate neural differentiation of embryonic stem cells (ESCs). Downregulation of importin-a1 and upregulation of importin-a3 and importin-a5 promote neural

differentiation of ESCs. Knockdown of lamin A facilitates reprogramming of mouse fibroblasts to induced pluripotency stem cells (iPSCs). Nups and/or nuclear-transport

receptors might be targeted to facilitate reprogramming. (B) Mutations in Nups are linked to various human disorders. Somatic cell reprogramming combined with gene

targeting might pave the way for using patient-derived autologous cells in cell therapy. (C) In aged post-mitotic cells, dysfunction of NPCs leads to an increased nuclear

permeability and leakage of cytoplasmic proteins into the nucleus. Abbreviations: AAAS, triple A syndrome; AF, atrial fibrillation; ANE, acute necrotizing encephalopathy;

IBSN, infantile bilateral striatal necrosis.

Opinion Trends in Molecular Medicine January 2014, Vol. 20, No. 1

Box 2. Nuclear pore components and human genetic roles of Nups in development, as well as towards develop-

disorders ing potential therapies (Figure 4B). Last but not least,

dysfunction of nuclear pores has been implicated in both

Mutations of nuclear-pore components as well as the nuclear

accelerated and normal ageing processes [31,32]. In post-

envelope have been implicated in various human genetic disorders

[29,30]. The first serious human genetic disorder that was dis- mitotic neurons, accumulated damage to long-life nuclear-

covered to be caused by a single nuclear-pore component was pore components during an organisms’ lifespan could cause

achalasia-addisonianism-alacrima syndrome (AAAS; triple A syn-

increased nuclear permeability and compromised cellular

drome). Triple A syndrome is caused by mutations in Aladin (H160R,

functions, which ultimately result in neurodegeneration

S263P, V313A, Q15K), a poorly understood component of nuclear-

(Figure 4C) [31]. Overall, the results reviewed here indi-

pore complexes [25]. Moreover, mutations in nucleoporins (Nups)

have been linked to neurological disorders. Missense mutation of cate that a better understanding of how nuclear pores

Nup62 causes autosomal recessive infantile bilateral striatal necro- regulate cell pluripotency and differentiation might pro-

sis (IBSN) [26]. The mutation Q391P is highly conserved in patients.

vide insights into human ageing, as well as ageing-associ-

It is suggested that the mutation influences the function of Nup62 in

ated disorders [33].

the degeneration of the basal ganglia in humans. Nup358 has also

been connected with neurological disorders [28]. Patients with the

mutation (T585M) are susceptible to acute necrotizing encephalo- Acknowledgments

pathy (ANE). However, the pathogenesis of the disease remains G.H.L. is supported by the Strategic Priority Research Program of the

unclear. Lastly, a mutation in Nup155 (R391H) affects its nuclear Chinese Academy of Sciences (XDA01020312), the National Basic Research

localization, reduces nuclear-envelope permeability and ultimately Program of China (973 Program, 2014CB964600), the National Natural

results in atrial fibrillation, which connects nuclear-pore complexes Science Foundation of China (NSFC) (81330008, 81271266, 31222039, and

to human cardiovascular diseases [27]. 31201111), the Thousand Young Talents program of China, the National

Laboratory of Biomacromolecules, and the State Key Laboratory of Drug

Research (SIMM1302KF-17). J.Q. is supported by the National Basic

differentiation, Nup98 interacts with the chromatin away Research Program of China (973 Program, 2014CB910500) and NSFC

(81371342). J.C.I.B. is supported by TERCEL-ISCIII-MINECO, CIBER,

from NPCs for an open surrounding. Currently, very little

Fundacion Cellex, the G. Harold and Leila Y. Mathers Charitable

is known about how the Nup98–chromatin interaction is

Foundation, the Leona M. and Harry B. Helmsley Charitable Trust, The

able to enhance gene transcription.

Glenn Foundation and the Ellison Medical Foundation.

Collectively, certain nuclear-pore components are able

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