Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA264478 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1618700.fastq.gz | Fastqsanger.gz | |||
| SRR1618696.fastq.gz | Fastqsanger.gz | |||
| SRR1618697.fastq.gz | Fastqsanger.gz | |||
| SRR1618698.fastq.gz | Fastqsanger.gz | |||
| SRR1618699.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 5 |
Similar Datasets
Project description:NUP98-HOXA9 role as oncogenic transcription factor
| PRJNA264476 | ENA
Project description:NUP98 FG repeats trigger hematopoietic malignancies when aberrantly fused to various DNA/chromatin binding domains. However, how these heterogeneous NUP98 fusions drive oncogenesis remains unclear. Here we fuse different NUP98 FG repeat compositions to dCas9 and establish that NUP98 FG repeats are sufficient to activate human genes via cooperative activity at human endogenous promoters. Further, we find that NUP98-FG repeats spontaneously undergo liquid-liquid phase separation and co-condensate with other transcriptional coactivators in human cells, which we show is indispensable for transcriptional activation. We also define a threshold of NUP98 FG repeat numbers required for biomolecular condensation and gene activation that is consistent with NUP98 FG repeat lengths observed across clinical cohorts. Using ChIP-seq and live cell imaging, we further demonstrate that although NUP98 FG repeats can robustly shuttle into cell nuclei, engagement with the human genome is directed solely through fusion partner. Interestingly, two frequent oncogenic fusions, NUP98-HOXA9 and NUP98-KDM5A exhibit discrete genomic engagement landscapes and gene-regulatory modes in that NUP98-HOXA9 initiates strong transcription via intragenic super enhancer-like binding and increased intrachromosomal contacts, while NUP98-KDM5A activates genes via strict localization to promoters. Additionally, in primary human HSCs, NUP98-HOXA9 and NUP98-KDM5A globally dysregulate transcription in a largely non-overlapping manner. Nevertheless, both oncogenic fusion proteins directly drive the inappropriate activation of core leukemia-associated oncogenes, which occurs coincident with the downregulation of genes associated with HSC lineage commitment. Altogether, our studies point toward a conserved core set of potential therapeutic targets driving NUP98-associated cancers and clarify the transcriptional and oncogenic role of aberrant NUP98 condensates.
2025-02-19 | GSE248061 | GEO
Project description:To study the oncogenic mechanism triggered by the leukemic fusion protein NUP98-HOXA9, we cloned the cDNA of NUP98-HOXA9 into a retroviral vector (pMSCV-IRES-GFP) and efficiently transduced the HEK293FT human cell line. We performed a ChIP-seq analysis to identify the DNA binding sites of NUP98-HOXA9. These results allowed us to demonstrate that NUP98-HOXA9 regulates the expression of genes involved in the development of Acute Myeloid Leukemia by directly interacting with their enhancer regions. We further investigated the functional contribution to the DNA binding profile of the two moieties that compose the fusion protein. We cloned the coding region of HOXA9 wt and NUP98 wt in the same retroviral vector, established two new cellular models, 293FT-HOXA9 and 293FT-NUP98, and performed separate ChIP-seq analyses. We demonstrated that both moieties contribute importantly to the regulation of the target genes.
2016-12-31 | GSE62586 | GEO
Project description:Development of cancer is intimately associated with genetic abnormalities that target proteins with intrinsically disordered regions (IDRs). In human hematological malignancies, recurrent chromosomal translocation of nucleoporin (NUP98 or NUP214) generates an aberrant chimera that invariably retains nucleoporin’s IDR, tandemly dispersed phenylalanine-andglycine (FG) repeats1-3. However, it remains largely elusive how unstructured IDRs contribute to oncogenesis. We here show that IDR or FG repeats harbored within NUP98-HOXA9, a homeodomain-containing transcription factor (TF) chimera recurrently detected in acute leukemia patients1,4,5, is essential for establishing nuclear liquid-liquid phase separation (LLPS) puncta and for inducing leukemic transformation of primary hematopoietic cells in vitro and in vivo. Strikingly, LLPS of NUP98-HOXA9 not only promotes chromatin occupancy of chimera TF oncoproteins but is also required for formation of a broad, ‘super-enhancer’-like binding pattern, typically seen at a battery of leukemia-related loci exemplified by HOX, MEIS and PBX genes, potentiating their transcriptional activation. An artificial HOX chimera, created by replacing NUP98’s FG repeats with an unrelated LLPSforming IDR of FUS6,7, had similar enhancement effects on chimera’s chromatin binding and target gene activation. Via Hi-C mapping, we further demonstrated that the phase-separated NUP98-HOXA9 protein assembly is able to induce formation of CTCF-independent chromatin looping enriched at leukemic oncogenes. Together, this report describes a proof-of-principle example wherein cancer acquires mutation to establish condensates of oncogenic TFs via a phase separation mechanism, which simultaneously enhances their chromatin targeting and induces organization of aberrant three-dimensional chromatin structure during tumorous transformation. As a range of LLPS-competent molecules are implicated in various human cancers, this mechanism can potentially be generalized to many malignant and diseased settings.
2021-04-22 | PXD023548 | Pride
Project description:We used ChIP-seq to examine the genome-wide binding of Nup98-HoxA9 and Crm1 in ES cells. Our analysis revealed that Nup98-HoxA9 is highly and preferentially targeted to specific chromatin sites, particularly near Hox cluster regions where the export factor Crm1 is originally prebound. chromatin immunoprecipitation
2016-01-04 | E-GEOD-68783 | biostudies-arrayexpress
Project description:By performing biotin-mediated chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) for two different NUP98 fusions, we defined the genome-wide direct binding sites of NUP98-HOXA9 or NUP98-HOXD13. To test whether NUP98 fusions and Mll1 were recruited to the same region of Hox genes promoters, Mll1 ChIP-seq analysis was carried out in murine NUP98-HOXA9 transformed cells using an anti-Mll1n antibody. In agreement with our results showing that NUP98-HOXA9 interacts with MLL1 in NSL/MLL1 complex, Mll1 binding targets significantly overlap with that of NUP98-HOXA9 at promoter region and gene body region. Given that MOF and MLL1 work in concert to modify H4K16ac and H3K4me3 at promoters, we further test whether H3K4me3 and H4K16ac marks are associated with NUP98-HOXA9-bound targets in murine NUP98-HOXA9 transformed cells by anti-H3K4me3 and anti-H4K16ac ChIP-seq. Our data show that both H3K4me3 and H4K16ac mark presents on NUP98-HOXA9 binding targets at promoters, and this is in line with the coordination role in the activities between MOF-mediated H4K16 acetylation and MLL/SET-mediated H3K4 methylation. In summary, our results confirmed that NUP98-HOXA9 and Mll1 are recruited to the same Hox loci, and this recruitment is associated with activating epigenetic marks, supporting the notion of the association between NUP98 fusions and NSL/Mll1 complex, suggesting that the recruitment of NUP98 fusions to the Hox gene loci maybe through MLL1.
2016-12-11 | GSE76001 | GEO
Project description:Development of cancer is intimately associated with genetic abnormalities that target proteins with intrinsically disordered regions (IDRs). In human hematological malignancies, recurrent chromosomal translocation of nucleoporin (NUP98 or NUP214) generates an aberrant chimera that invariably retains nucleoporin?s IDR, tandemly dispersed phenylalanine-and-glycine (FG) repeats. However, it remains elusive how unstructured IDRs contribute to oncogenesis. We show that IDR harbored within NUP98-HOXA9, a homeodomain-containing transcription factor (TF) chimera recurrently detected in leukemias, is essential for establishing liquid-liquid phase separation (LLPS) puncta of chimera and for inducing leukemic transformation. Strikingly, LLPS of NUP98-HOXA9 not only promotes chromatin occupancy of chimera TFs but is also required for formation of a broad, ?super-enhancer?-like binding pattern, typically seen at a battery of leukemogenic genes, potentiating their transcriptional activation. Artificial HOX chimera (FUS-HOXA9), created by replacing NUP98?s FG repeats with an unrelated LLPS-forming IDR of FUS, had similar enhancement effects on chimera?s genome-wide binding and target gene activation. Hi-C mapping further demonstrated that phase-separated NUP98-HOXA9 induces CTCF-independent chromatin looping enriched at proto-oncogenes. Together, this report describes a proof-of-principle example wherein cancer acquires mutation to establish oncogenic TF condensates via phase separation, which simultaneously enhances their genomic targeting and induces organization of aberrant three-dimensional chromatin structure during tumorous transformation. As LLPS-competent molecules are frequently implicated in diseases, this mechanism can potentially be generalized to many malignant and pathological settings.
2021-04-19 | GSE144076 | GEO
Project description:Leukemia is a complex malignancy with hundreds of distinct mutations associated with disease development. Studies have shown that oncogenes cooperate to promote leukemia transformation, however, the downstream effectors of this cooperation are largely unknown. Using a genetically defined mouse model of acute leuekmia, we investigated the regulated of genes downstream of the cooperative oncogenic interaction between BCR-ABL and NUP98-HOXA9 and identified a unique gene signature abberrantly expression in leukemia. Total RNA was isolated from hematopoietic cells transduced with BCR-ABL and Nup98-HOXA9 retroviruses and transplanted into recipient mice. Bone marrow cells were purified by GFP (BCR-ABL) and YFP (NUP98-HOXA9) using FACS.
2012-05-10 | E-GEOD-37907 | biostudies-arrayexpress
Project description:We used ChIP-seq to examine the genome-wide binding of Nup98-HoxA9 and Crm1 in ES cells. Our analysis revealed that Nup98-HoxA9 is highly and preferentially targeted to specific chromatin sites, particularly near Hox cluster regions where the export factor Crm1 is originally prebound.
2016-01-04 | GSE68783 | GEO
Project description:Development of NUP98-HOXA9 gene expression signatures
| PRJNA264479 | ENA