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

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

PROVIDER: PRJNA498296 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8105410.fastq.gz	Fastqsanger.gz
	SRR8105401.fastq.gz	Fastqsanger.gz
	SRR8105402.fastq.gz	Fastqsanger.gz
	SRR8105403.fastq.gz	Fastqsanger.gz
	SRR8105404.fastq.gz	Fastqsanger.gz

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

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

| PRJNA498297 | ENA

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: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 | GSE121740 | GEO

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

2019-06-12 | GSE121741 | GEO

Release of paused RNA-Polymerase II at specific introns and chromatin domains favors spontaneous DNA double strand break formation and predicts cancer translocations [ChIP-seq & BLISS]

Project description:Transcriptional activation leads to transient accumulation of DNA Double Strand Breaks (DSBs), which might promote formation of chromosomal translocations. We report here the genomic distribution of DSBs in non-transformed mammary cells grown under unperturbed conditions, using genome-wide Breaks Labeling In Situ and Sequencing (BLISS). We found thousands of high-confidence DSBs, which were enriched at the promoters of a subset of moderately- to highly-transcribed genes (fragile promoters) and co-localized with Topoisomerase II beta. Analyses of DSB-predictive features identified gene length and paused RNA Polymerase II, but not transcription, as critical factors (84% prediction accuracy). Analyses of DSB signaling and repair factors showed high levels of XRCC4, but not of gammaH2AX and NBS1, and no RAD51. Finally, the observed DSBs were predictive of a significant fraction of the recurrent translocations found in human breast cancers. These data suggest that, in normal cells, basal transcription from a specific class of promoters entails accumulation of TOP2B, leading to unresolved DSBs and increased probability of chromosomal translocations.

2019-03-12 | GSE93038 | GEO

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

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

Expression data from conditionally immortalized MLL-AF9 and MLL-ENL hematopoietic progenitor cells following loss of MLL-fusion oncogene

Project description:Chromosomal translocations encoding the MLL-AF9 and MLL-ENL fusion transcription factors are prevalent in infant acute leukaemia and therapy-related leukaemia. In order to conditionally express the MLL-fusion oncogene in primary haematopoietic progenitor cells (HPC), retroviral delivery of the Tet-off expression system was used (Horton et al., Cancer Res, 2005). Treatment of the conditional cells with Doxycycline caused a decrease in MLL-AF9/ENL mRNA and protein expression, and resulted in terminal differentiation of the cells. By analysing global changes in gene expression after treatment of cells with Doxycycline we were able to identify a number of potential transcriptional target genes of the MLL-AF9 and MLL-ENL fusion oncogenes.

2014-12-01 | GSE59236 | GEO

Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo

Project description:Chromosomal translocations affecting Mixed Lineage Leukemia (MLL) gene result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report development of novel, highly potent and orally bioavailable small molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, show their profound effects in MLL leukemia cells and substantial survival benefit in mice models of MLL leukemia. Finally, we demonstrate efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate for the first time that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.

2017-08-21 | GSE60673 | GEO

The quantitative analysis of transcriptomes derived from MLL-AF10 flox cells and MLL-AF10 (Tip60 flox/flox, Cre-ERT2) cells with or without the treatment of 4-OHT

Project description:Chromosome translocations involving the MLL gene are common rearrangements in leukemia. Such translocations fuse the MLL 5’-region in frame to partner genes , and the resultant fusion proteins can cause MLL-related leukemia. MLL-fusions activate transcription of target genes such as the HoxA cluster and Meis1, but the underlying mechanisms remain elusive. We found that the MLL-AF10 fusion recruits Tip60 to the Hoxa9 locus, where it acetylates H2A.Z, thereby promoting Hoxa9 expression. Following conditional deletion of Tip60, hypoacetylation of H2A.Z was accompanied by recruitment of Ezh2, the catalytic subunit of PRC2, suggesting that nucleosomes with hypoacetylated H2A.Z are the preferential targets of Ezh2. Our findings suggest that MLL-AF10 achieves active chromatin states by recruiting Tip60, which acetylates H2A.Z to prevent gene silencing by Ezh2.

2021-06-30 | GSE142558 | GEO

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