A Conserved Role for Human Nup98 in Altering Chromatin Structure and Promoting Epigenetic Transcriptional Memory

Light, William H.; Freaney, Jonathan E.; Sood, Varun; Thompson, Abbey; D’Urso, Agustina; Horvath, Curt M.; Brickner, Jason H.

doi:10.1371/journal.pbio.1001524

Cited by 178 publications

(327 citation statements)

References 90 publications

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“…Using two independent assays, we found no defect in nuclear export or import on depletion of Nup98 or several other nuclear pore proteins. This finding is consistent with two recent studies that found no role for Nup98 in nuclear transport when Nup98 was compromised (22,28). In addition, using single-molecule RNA FISH, we detected no defect in nuclear export of B52 or CG9008 mRNA on depletion of Nup98.…”

Section: Discussionsupporting

confidence: 93%

“…Studies have shown that Nup98 localizes predominantly to the nuclear pore complex, but has an additional population in the nucleoplasm and can exhibit altered nuclear distribution in response to some stimuli, such as developmental signaling or IFN-γ (19,20,22,34). In our system, we found that Nup98 levels are increased on viral infection (Fig.…”

Section: Resultssupporting

confidence: 49%

“…These antiviral phenotypes were ascribed to transport defects; however, it has not been explored whether Nup98 also directly regulates the induction of antiviral primary response genes. Interestingly, a recent study found that Nup98 impacts the regulation of IFN-γ-responsive genes (22). In this study, Nup98 was required to set the reactivation state of IFN-γ-responsive genes without affecting the initial activation (22).…”

Section: Discussionmentioning

confidence: 66%

“…Recent studies have revealed a direct role for Nup98 in gene expression, particularly in the transcriptional regulation of developmental and immune genes (19,20,22,35). Thus, we hypothesized that Nup98 may similarly regulate the expression of antiviral genes independent of its role in nucleo-cytoplasmic transport.…”

Section: Resultsmentioning

confidence: 97%

“…that Nup98 is similarly involved in the transcriptional regulation of IFN-γ-induced gene expression (22), suggesting that the transcriptional roles of Nups may be involved in immunity.…”

Section: Significancementioning

confidence: 99%

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Nup98 promotes antiviral gene expression to restrict RNA viral infection in Drosophila

Panda

Pascual-Garcia²,

Dunagin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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In response to infection, the innate immune system rapidly activates an elaborate and tightly orchestrated gene expression program to induce critical antimicrobial genes. While many key players in this program have been identified in disparate biological systems, it is clear that there are additional uncharacterized mechanisms at play. Our previous studies revealed that a rapidly-induced antiviral gene expression program is active against disparate human arthropod-borne viruses in Drosophila. Moreover, one-half of this program is regulated at the level of transcriptional pausing. Here we found that Nup98, a virus-induced gene, was antiviral against a panel of viruses both in cells and adult flies since its depletion significantly enhanced viral infection. Mechanistically, we found that Nup98 promotes antiviral gene expression in Drosophila at the level of transcription. Expression profiling revealed that the virus-induced activation of 36 genes was abrogated upon loss of Nup98; and we found that a subset of these Nup98-dependent genes were antiviral. These Nup98-dependent virus-induced genes are Cdk9-dependent and translation-independent suggesting that these are rapidly induced primary response genes. Biochemically, we demonstrate that Nup98 is directly bound to the promoters of virus-induced genes, and that it promotes occupancy of the initiating form of RNA polymerase II at these promoters, which are rapidly induced on viral infection to restrict human arboviruses in insects.innate immunity | nuclear pore | nucleoporin | pol II regulation | P-TEFb

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Section: Discussionsupporting

confidence: 93%

Section: Resultssupporting

confidence: 49%

Section: Discussionmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 97%

“…that Nup98 is similarly involved in the transcriptional regulation of IFN-γ-induced gene expression (22), suggesting that the transcriptional roles of Nups may be involved in immunity.…”

Section: Significancementioning

confidence: 99%

See 3 more Smart Citations

Nup98 promotes antiviral gene expression to restrict RNA viral infection in Drosophila

Panda

Pascual-Garcia²,

Dunagin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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You are who your friends are—nuclear pore proteins as components of chromatin‐binding complexes

Capelson

2023

FEBS Letters

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Nuclear pore complexes (NPCs) are large multi‐component protein complexes that are embedded in the nuclear envelope, where they mediate nucleocytoplasmic transport. In addition to supporting transport, nuclear pore components, termed nucleoporins (Nups), can interact with chromatin and influence genome function. A subset of Nups can also localize to the nuclear interior and bind chromatin intranuclearly, providing an opportunity to investigate chromatin‐associated functions of Nups outside of the transport context. This review focuses on the gene regulatory functions of such intranuclear Nups, with a particular emphasis on their identity as components of several chromatin regulatory complexes. Recent proteomic screens have identified Nups as interacting partners of active and repressive epigenetic machinery, architectural proteins, and DNA replication complexes, providing insight into molecular mechanisms via which Nups regulate gene expression programs. This review summarizes these interactions and discusses their potential functions in the broader framework of nuclear genome organization.

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NUP98 oncofusions in myeloid malignancies: An update on molecular mechanisms and therapeutic opportunities

Rasouli,

Troester,

Grebien

et al. 2024

HemaSphere

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Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a heterogeneous molecular landscape. In the pediatric context, the NUP98 gene is a frequent target of chromosomal rearrangements that are linked to poor prognosis and unfavorable treatment outcomes in different AML subtypes. The translocations fuse NUP98 to a diverse array of partner genes, resulting in fusion proteins with novel functions. NUP98 fusion oncoproteins induce aberrant biomolecular condensation, abnormal gene expression programs, and re‐wired protein interactions which ultimately cause alterations in the cell cycle and changes in cellular structures, all of which contribute to leukemia development. The extent of these effects is steered by the functional domains of the fusion partners and the influence of concomitant somatic mutations. In this review, we discuss the complex characteristics of NUP98 fusion proteins and potential novel therapeutic approaches for NUP98 fusion‐driven AML.

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A Conserved Role for Human Nup98 in Altering Chromatin Structure and Promoting Epigenetic Transcriptional Memory

Abstract: In yeast and humans, interaction of a nuclear pore protein with promoters alters chromatin structure and allows RNA polymerase II to bind, poising them for faster reactivation for several generations.

Cited by 178 publications

References 90 publications

Nup98 promotes antiviral gene expression to restrict RNA viral infection in Drosophila

Nup98 promotes antiviral gene expression to restrict RNA viral infection in Drosophila

You are who your friends are—nuclear pore proteins as components of chromatin‐binding complexes

NUP98 oncofusions in myeloid malignancies: An update on molecular mechanisms and therapeutic opportunities

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