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Circular RNAs drive oncogenic chromosomal translocations through R-loop-mediated genome instability

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125986 | GEO | 2023/05/01

REPOSITORIES: GEO

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Circular RNAs drive oncogenic chromosomal translocations through R-loop-mediated genome instability [ATAC-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). Single replicates of each cell line underwent ATAC-seq

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Circular RNAs drive oncogenic chromosomal translocations through R-loop-mediated genome instability [RNA-seq 2]

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). Biological triplicates of each cell line, or individual representatives from tumour cells purified from mouse xenograft experiments (labeled tumour) underwent mRNA sequencing

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Circular RNAs drive oncogenic chromosomal translocations through R-loop-mediated genome instability

Project description:Circular RNAs drive oncogenic chromosomal translocations through R-loop-mediated genome instability

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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]

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