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Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations

ABSTRACT: Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations

PROVIDER: PRJNA498297 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8105410.fastq.gz	Fastqsanger.gz
	SRR8104571_1.fastq.gz	Fastqsanger.gz
	SRR8104571_2.fastq.gz	Fastqsanger.gz
	SRR8105401.fastq.gz	Fastqsanger.gz
	SRR8104572_1.fastq.gz	Fastqsanger.gz

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Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations [RNA-Seq]

Project description:Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations [RNA-Seq]

| PRJNA498294 | ENA

Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations [BLISS-Seq]

Project description:Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations [BLISS-Seq]

| PRJNA498296 | ENA

Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations [RNA-Seq]

Project description:How spatial chromosome organization influences genome integrity is still poorly understood. Here we show that DNA double-strand breaks (DSBs) mediated by topoisomerase 2 (TOP2) activities, are enriched at chromatin loop anchors with high transcriptional activity. Recurrent DSBs occur at CTCF/cohesin bound sites at the bases of chromatin loops and their frequency positively correlates with transcriptional output and directionality. The physiological relevance of this preferential positioning is indicated by the finding that genes recurrently translocating to drive leukemias, are highly transcribed and are enriched at loop anchors. These genes accumulate DSBs at recurrent hot spots that give rise to chromosomal fusions relying on the activity of both TOP2 isoforms and on transcriptional elongation. We propose that transcription and 3D chromosome folding jointly pose a threat to genomic stability, and are key contributors to the occurrence of genome rearrangements that drive cancer.

2019-06-12 | GSE121741 | GEO

Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations [BLISS-Seq]

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Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-06-12 | GSE121742 | GEO

Circular RNAs drive oncogenic chromosomal translocations through R-loop-mediated genome instability [ncRNA-seq]

Project description:Studying the role of circular RNAs in cancer initiation by profiling the interaction of circRNAs with DNA in human cells. The first step of oncogenesis is the acquisition of a repertoire of genetic mutations to initiate and sustain the malignancy. An important example of this initiation phase in leukaemia is the formation of a potent oncogene by chromosomal translocations between the histone methyltransferase Mixed Lineage Leukaemia (MLL) gene and one of over 100 translocation partner genes. Here we show that circular RNAs (circRNAs) - which are a family of covalently-closed, alternatively-spliced RNA molecules - bind DNA, forming circRNA:DNA hybrids (circR-loops) at their cognate loci, and promote transcriptional pausing and DNA breaks. The MLL recombinome concentrates these circR-loops and by overexpressing circRNAs from MLL in human cells we could generate de novo chromosomal translocations, mimicking the MLL recombinome. We anticipate our findings will illuminate this critical phase in cancer initiation and provide a framework to investigate the action of endogenous RNA molecules underlying various genetic aberrations through a process of Endogenous RNA-Directed DNA Damage (ER3D).

2023-05-02 | GSE217126 | GEO

Circular RNAs drive oncogenic chromosomal translocations through R-loop-mediated genome instability [DRIP-seq]

2023-05-01 | GSE125985 | GEO

Circular RNAs drive oncogenic chromosomal translocations through R-loop-mediated genome instability [RNA-seq]

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Circular RNAs drive oncogenic chromosomal translocations through R-loop-mediated genome instability [ATAC-Seq]

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Therapeutic targeting MLL degradation pathways in MLL-rearranged leukemia

Project description:Chromosomal translocations of the mixed-lineage leukemia (MLL) gene with various partner genes result in aggressive leukemia with dismal outcomes. Despite similar expression at the mRNA level from the wild-type and chimeric MLL alleles, the chimeric protein is more stable. We report that UBE2O functions in regulating the stability of wild-type MLL in response to interleukin-1 signaling. Targeting wild-type MLL degradation impedes MLL leukemia cell proliferation, and it downregulates a specific group of target genes of the MLL chimeras and their oncogenic cofactor, the super elongation complex. Pharmacologically inhibiting this pathway substantially delays progression, and it improves survival of murine leukemia through stabilizing wild-type MLL protein, which displaces the MLL chimera from some of its target genes and, therefore, relieves the cellular oncogenic addiction to MLL chimeras. Stabilization of MLL provides us with a paradigm in the development of therapies for aggressive MLL leukemia and perhaps for other cancers caused by translocations.

2017-01-06 | GSE89485 | GEO

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