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Genome-wide maps of Nup98 binding in human embryonic stem cells, neural progenitors, neuron cells and lung fibroblasts

ABSTRACT: Recent evidence suggests that nucleoporins, well known components that control nucleo-cytoplasmic trafficking, have wide-ranging functions in developmental gene regulation that potentially extend beyond their role in nuclear transport. Whether the unexpected role of nuclear pore proteins in transcription regulation, which initially has been described in fungi and flies, also applies to human cells is unknown. Here we show at a genome-wide level that the nuclear pore protein NUP98 associates with developmentally regulated genes active during human embryonic stem cell differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE48996 | GEO | 2013/07/17

SECONDARY ACCESSION(S): PRJNA212541

REPOSITORIES: GEO

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Genome-wide maps of Nup98 binding in human embryonic stem cells, neural progenitors, neuron cells and lung fibroblasts

Project description:Recent evidence suggests that nucleoporins, well known components that control nucleo-cytoplasmic trafficking, have wide-ranging functions in developmental gene regulation that potentially extend beyond their role in nuclear transport. Whether the unexpected role of nuclear pore proteins in transcription regulation, which initially has been described in fungi and flies, also applies to human cells is unknown. Here we show at a genome-wide level that the nuclear pore protein NUP98 associates with developmentally regulated genes active during human embryonic stem cell differentiation. Examination of Nup98 binding using multiple Nup98 antibodies in four cell types, three of which are related by direct lineage.

2013-07-17 | E-GEOD-48996 | biostudies-arrayexpress

Functional interaction of chromatin with nucleoporins in Drosophila

Project description:Nuclear pore complexes (NPCs) mediate transport across the nuclear envelope. In yeast, they have also been proposed to interact with active genes, attracting or retaining them at the nuclear periphery. However, some NPC components (nucleoporins) in higher eukaryotes are also found in the nucleoplasm, with so far unknown function. Therefore, we have functionally distinguished between nucleoporin-chromatin interactions at the NPC and within the nucleoplasm in Drosophila. For this we analyzed genomic interactions of full-length nucleoporins Nup98, Nup50 and Nup62 and nucleoplasmic and NPC-tethered forms of Nup98. We found that nucleoporins predominantly interacted with transcriptionally active genes inside the nucleoplasm. A smaller set of non-active genes interacted with the NPC. We identified a direct role for nucleoplasmic Nup98 in stimulating gene expression, as genes downregulated upon Nup98 depletion were activated upon nucleoplasmic Nup98 overexpression and showed strong nucleoplasmic Nup98 interaction. Thus, nucleoporins stimulate gene expression away from the NPC by interacting with genes inside the nucleoplasm.

2010-03-01 | GSE19307 | GEO

Nup93 modulates spatiotemporal dynamics and function of the HOXA gene cluster during differentiation

Project description:The central role of nucleoporins is to transport RNA and proteins. In addtion, nucleoporins are also involved in gene regulation. Furthermore, nucleoporins - Nup93, Nup153, Nup98 and Nup210, directly associate with developmental genes and regulate developmental processes by direct association with developmental genes. Here, we identified genome wide binding profile of Nup93 - a core component of the nuclear pore complex in colorectal cancer cell line DLD-1 by ChIP-seq. Our ChIP-seq analysis revealed significant association of Nup93 with developmental genes and known enhancer marks such as H3K4me1 and H3K27Ac . We found that Nup93 shares binding sites with CTCF - the well known chromatin organizer, suggesting a functional overlap between Nup93 and CTCF in the organization and regulation of developmental gene expression such as the the HOXA gene cluster.

2021-12-06 | GSE130656 | GEO

Global mouse gene expression data from NUP98-NSD1/FLT3-ITD AML samples and Normal Wild Type whole bone marrow and Normal Wild Type lineage negative bone marrow samples assessed by Bulk RNA-Seq.

Project description:Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy driven largely by gene mutations and epigenetic modifications. The Nucleoporin 98kDa (NUP98) gene is a component of the nuclear pore complex that also plays a role as an intranuclear transcription scaffold. Fusion genes involving NUP98 have been recognized in a wide array of hematologic malignancy, most commonly AML4. Among over 30 partner genes known to be fused to NUP98 in human leukemia, NSD1 (for Nuclear receptor-binding SET Domain protein 1) (NSD1) is the most common. Patients with NUP98::NSD1 gene fusions have a poor prognosis, and the leukemic blasts frequently have an internal tandem duplication (ITD) of the FMS-related tyrosine kinase 3 gene (FLT3) gene accompanying the NUP98::NSD1 fusion. Previous reports have utilized BM transduction with retroviral vectors followed by transplantation into recipient mice to model AML driven by a NUP98::NSD1 fusion. Given that genetically engineered mice offer certain advantages over retroviral transduction models, such as consistent transgene expression and integration effects, lack of ionizing radiation, and transferability between investigators, we generated NUP98::Nsd1 transgenic mice.

2023-07-12 | GSE229501 | GEO

Nuclear Condensation of NUP98-Fusion Proteins drives leukemogenic gene expression NUP98-fusion protein drive oncogenic gene expression via nuclear/biomolecular condensation

Project description:NUP98-fusion proteins cause leukemia via unknown molecular mechanisms. All NUP98-fusion proteins share an intrinsically disordered region (IDR) featuring >35 repeats of Phenylalanine-Glycine (FG) in the NUP98 N-terminus. Conversely, C-terminal NUP98-fusion partners often have critical functions in gene control. Given these structural features we hypothesized that mechanisms of oncogenic transformation by NUP98-fusion proteins are hard-wired in their protein interactomes. Affinity purification coupled to mass spectrometry and confocal imaging of five distinct NUP98-fusion proteins revealed that conserved interactors were enriched for proteins involved in biomolecular condensation and that they co-localized with NUP98-fusion proteins in nuclear puncta. We developed biotinylated isoxazole-mediated condensome mass spectrometry (biCon-MS) to show that NUP98-fusion proteins alter the global composition of biomolecular condensates. An artificial FG-repeat-containing fusion protein phenocopied the nuclear localization patterns of NUP98-fusion proteins and their capability to drive oncogenic gene expression programs. Thus, we propose that IDR-containing fusion proteins uniquely combine biomolecular condensation with transcriptional control to induce cancer.

2020-12-23 | PXD022518 | Pride

Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion

Project description:The dysregulation of plant homeodomain (PHD) fingers has been implicated in several human diseases, including cancer. In a subset of aggressive acute myeloid leukemia (AML), chromosomal translocations that involve nucleoporin 98 (NUP98), a component of the nuclear pore complex, and a PHD finger-containing protein, such as KDM5A/JARID1A, PHF23 and BPTF, generate potent oncoproteins (namely NUP98-KDM5A, NUP98-PHF23 and NUP98-BPTF; or together termed as NUP98-PHD fusions) that are able to arrest hematopoietic differentiation and induce acute myeloid leukemia in murine models. In these processes, a PHD finger that specifically recognizes H3K4me3/2 marks was essential for leukemogenesis. Mutations in PHD fingers that abrogated H3K4me3 binding also abolished leukemic transformation. An overlap of NUP98-KDM5A oncoprotein binding sites and H3K4me3-positive loci at the Hoxa/b gene clusters and Meis1 in ChIP-seq together with NMR analysis of the H3K4me3-binding sites of the PHD fingers from PHF23, KDM5A and BPTF suggests a common PHD finger-dependent mechanism that promotes leukemogenesis by this type of NUP98-PHD finger fusions. Disulfiram (DS), a small molecule compound that directly targets the PHD finger, shows anti-proliferation effects in AML cells expressing NUP98-PHD through the conserved inhibitory mechanism. Our findings highlight the direct correlation between the abilities of NUP98-PHD finger fusion chimeras to associate with H3K4me3-enriched chromatin and leukemic transformation.

2020-07-13 | GSE146693 | GEO

Nucleoporin Nup153 Regulates Stem Cell Pluripotency through Gene Silencing

Project description:Nucleoporins (Nups) are a family of proteins best known as the constituent building blocks of nuclear pore complexes (NPCs), the transport channels that mediate nuclear transport. Recent evidence suggest that several Nups have additional roles in controlling the activation and silencing of developmental genes, however, the mechanistic details of these functions remain poorly understood. Here, we show that depletion of Nup153 in mouse embryonic stem cells (mESCs) causes the de-repression of developmental genes and induction of early differentiation. This loss of pluripotency is not associated with defects in global nucleo-cytoplasmic transport activity. Instead, Nup153 binds to the transcriptional start site (TSS) of developmental genes and mediates the recruitment of the polycomb repressive complex 1 (PRC1) to its target loci. Our results reveal a nuclear transport-independent role of Nup153 in maintaining stem cell pluripotency and introduce a role of NPC proteins in mammalian epigenetic gene silencing. RNA-seq, ChIP-Seq, and DamID-Seq for Nup153, Oct4, and key chromatin regulators in mouse ES cells and neural progenitors

2015-06-19 | E-GEOD-64008 | biostudies-arrayexpress

Distinct Basket Nucleoporins roles in Nuclear Pore Function and Gene Expression

Project description:Nuclear pore complexes (NPCs) are important for cellular functions beyond nucleocytoplasmic trafficking, including genome organization and gene expression. This multi-faceted nature and the slow turnover of NPC components complicates investigations of how individual nucleoporins act in these diverse processes. To address this question, we used an Auxin-Induced Degron (AID) system to distinguish roles of basket nucleoporins Nup153, Nup50 and Tpr. Here, we provide MS data for the Nuclear Pore-enriched fraction of human DLD-1 cells, expressing CRISPR-engeneered degron, fused with the endogenous locus of corresponding basket NUPs, in the absence or presence of Auxin.

2020-06-30 | PXD020075 | Pride

SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic that is a serious global health threat. Evasion of interferon-mediated antiviral signaling is a common defense strategy that pathogenic viruses use to replicate and propagate in their host. In this study, we show that SARS-CoV-2 is able to efficiently block STAT1 and STAT2 nuclear translocation in order to impair transcriptional induction of interferon (IFN) stimulated genes (ISGs). Our results demonstrate that the viral accessory protein Orf6 exerts this anti-IFN activity. We found that SARS-CoV-2 Orf6 localizes at the nuclear pore complex (NPC) where it directly interacts with Nup98-Rae1 via its C-terminal domain to impair docking of cargo-receptor complexes and disrupt nuclear import functions. In addition, we show that a methionine-to-arginine substitution at residue 58 impairs Orf6 binding to the Nup98-Rae1 complex and abolishes its IFN antagonistic function. All together our data unravel a new mechanism of viral antagonism in which a virus hijacks the Nup98-Rae1 complex to overcome the antiviral action of IFN.

2020-10-20 | GSE159593 | GEO

Transcriptome profiles of POM121-knockout prostate cancer cell lines

Project description:Nucleoporins are major constituents of nuclear pore complexes, molecular conglomerates embedded within the nuclear envelope that participate in bidirectional trafficking between nucleus and cytoplasm, chromatin silencing and organization, and transcriptional regulation . This functional vantage point is of utmost importance for fundamental cell processes such as intracellular signaling, cell migration, DNA repair and cell division, all of which can be impaired when the molecular identity of the NE and nuclear pore complex is compromised, as seen in cancer. Here we identify a nucleoporin POM121 as a key regulator of proliferation, tumourigenesis, and survival in chemoresistant prostate cancer. Mechanistically, POM121 regulates nuclear transport of specific survival-conferring transcription factors (MYC and E2F1) and androgen receptor that have been previously linked with advanced stages of prostate cancer. POM121-mediated deregulation of nucleocytoplasmic transport occurs through its interaction with Importin β, which serves as a pharmacological target that decreases tumour growth, sensitizes the tumor cells to standard chemotherapy, and improves survival of patient-derived xenograft mice. These results indicate that nuclear pore complex represents a novel mechanism of chemoresistance, which can be therapeutically targetable in aggressive prostate cancer.

2018-08-22 | GSE103637 | GEO

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