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Regulatory landscape fusion in rhabdomyosarcoma by interactions between the PAX3 promoter and FOXO1 regulatory elements

ABSTRACT: Regulatory landscape fusion in rhabdomyosarcoma by interactions between the PAX3 promoter and FOXO1 regulatory elements

PROVIDER: PRJNA285501 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR2046963.fastq.gz	Fastqsanger.gz
	SRR2046964.fastq.gz	Fastqsanger.gz
	SRR2046965.fastq.gz	Fastqsanger.gz
	SRR2046966.fastq.gz	Fastqsanger.gz
	SRR2046967.fastq.gz	Fastqsanger.gz

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Regulatory landscape fusion in rhabdomyosarcoma by interactions between the PAX3 promoter and FOXO1 regulatory elements

Project description:Results: Using a combination of 4C-seq datasets, we were able to model the three-dimensional organisation of the translocated chromosome in a PAX3:FOXO1 fusion-positive alveolar rhabdomyosarcoma cell line. We show that PAX3 and FOXO1 regulatory landscapes fuse into a novel TAD, allowing the PAX3 promoter to interact ectopically with FOXO1 sequences with potential enhancer function. The borders of this novel TAD correspond to the original 5'- and 3'- borders of the PAX3 and FOXO1 TADs, respectively, suggesting that TAD organisation precedes the formation of regulatory long-range interactions. Conclusions: Our results suggest that the chromosomal translocation that leads to ARMS development generates a novel TAD that favours ectopic PAX3:FOXO1 oncogene activation in non-PAX3 territories, which may be an essential step in the tumorigenic process, as expression in a particular cell type, the often elusive cell-of-origin, may be required for disease development.

2017-04-17 | GSE69439 | GEO

KDM3B inhibitors disrupt PAX3-FOXO1 oncogenic activity in fusion positive rhabdomyosarcoma.

Project description:Fusion-positive alveolar rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. We screened 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, PFI-63. RNA-seq, ATAC-seq, and docking analyses implicated histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirmed the inhibition of multiple KDMs with highest selectivity for KDM3B. Structural similarity search of PFI-63 identified PFI-90 with improved solubility and potency. Biophysical binding of PFI-90 to KDM3B was demonstrated using NMR and SPR. PFI-90 suppressed the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopied PFI-90 effects. Thus, we report novel KDM inhibitors with highest specificity for KDM3B. Its potent suppression of PAX3-FOXO1 activity can be exploited as a new therapeutic approach for FP-RMS and other transcriptionally driven cancers.

2023-12-31 | GSE219199 | GEO

BioID HEK293T PAX3-FOXO1 proximity labelling

Project description:PAX3-FOXO1 is a fusion transcription factor that is the main driver of tumorigenesis leading to the development of alveolar rhabdomyosarcoma (aRMS). Since aRMS cells are addicted to PAX3-FOXO1 activity, the fusion protein also represents a major target for therapeutic interference, which is however challenging as transcription factors usually cannot be inhibited directly by small molecules. Hence, characterization of the biology of PAX3-FOXO1 might lead to the discovery of new possibilities for an indirect inhibition of its activity. Here, our goal was to characterize the proteomic neighborhood of PAX3-FOXO1 and to find candidates potentially affecting its activity and tumor cell viability. Towards this aim, we expressed BirA fused versions of PAX3-FOXO1 (N- and C-terminal) in HEK293T cells under presence of biotin. In the control setup, we expressed the BirA enzyme alone. After Streptavidin purification of biotinylated proteins, we performed mass spectrometry and quantified relative abundances compared to control conditions. This enabled us to determine PAX3-FOXO1 proximal proteins, which we investigated further in orthogonal endogenous systems.

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KDM3A/Ets1 epigenetic axis contributes to PAX3/FOXO1-driven and independent disease-promoting gene expression in fusion-positive Rhabdomyosarcoma

Project description:The goal of this study was to define functional and gene regulatory effects of KDM3A and Ets1, and their relationship to the PAX3/FOXO1 driver oncofusion, in fusion-positive Rhabdomyosarcoma.

2020-07-07 | GSE153852 | GEO

Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma [RNAseq_LHCN_hg19]

Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic PAX3–FOXO1 fusion protein, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability for PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth by disrupting the expression of CRC TFs caused by epigenetic alterations of PAX3–FOXO1-governed super enhancers. Combining KDM4B inhibition with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable mechanism required for maintenance of PAX3-FOXO1-related CRC TF network, which may translate to a novel therapeutic approach for fusion-positive RMS.

2022-09-06 | GSE201224 | GEO

PAX3-FOXO1 regulated microRNAs contribute to the pathogenesis of alveolar rhabdomyosarcoma

Project description:Interrogation of microRNA expression and regulation by PAX3-FOXO1 in Fusion-Positive Rhabdomyosarcoma.

2018-01-26 | GSE97553 | GEO

Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma [RNA-Seq]

2022-09-06 | GSE198755 | GEO

Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma [CUT&Tag]

2022-09-06 | GSE198754 | GEO

Expression data for analysis of genes affected by PAX3-FOXO1 in alveolar rhabdomyosarcoma cell line Rh4

Project description:PAX3-FOXO1 is a fusion transcription factor characteristic for the majority of alveolar rhabdomyosarcoma tumors. It is the main oncogenic driver and deregulates expression of PAX3 target genes. The PAX3-FOXO1 target gene signature was determined in the Rh4 alveolar rhabdomyosarcoma cell line.

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Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma [CUT&RUN, 2]

2022-09-06 | GSE198753 | GEO