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Epigenome editing of microsatellite repeat enhancers reveals specific regulatory functions and tumor dependencies

ABSTRACT: Epigenome editing of microsatellite repeat enhancers reveals specific regulatory functions and tumor dependencies

PROVIDER: PRJNA418451 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6293410.fastq.gz	Fastqsanger.gz
	SRR6293420.fastq.gz	Fastqsanger.gz
	SRR6293430.fastq.gz	Fastqsanger.gz
	SRR6293411.fastq.gz	Fastqsanger.gz
	SRR6293421.fastq.gz	Fastqsanger.gz

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Epigenome editing of microsatellite repeat enhancers reveals specific regulatory functions and tumor dependencies [ChIP-Seq]

Project description:Epigenome editing of microsatellite repeat enhancers reveals specific regulatory functions and tumor dependencies [ChIP-Seq]

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Epigenome editing of microsatellite repeat enhancers reveals specific regulatory functions and tumor dependencies [NRO-Seq]

Project description:Epigenome editing of microsatellite repeat enhancers reveals specific regulatory functions and tumor dependencies [NRO-Seq]

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Epigenome editing of microsatellite repeat enhancers reveals specific regulatory functions and tumor dependencies [NRO-Seq]

Project description:Various types of repetitive sequences are dysregulated in cancer but their contributions to oncogenesis are yet to be determined. Here we combine nascent transcription profiling with epigenome editing to test the function of GGAA microsatellites in Ewing sarcoma, a pediatric bone cancer where the oncogenic fusion protein EWS-FLI1 induces chromatin features of active enhancers at this class of repeats. Silencing of chromatin through epigenome editing at specific GGAA repeats abolished local nascent transcription, decreased the expression of neighboring target genes and, in the case of a repeat associated with the SOX2 locus, reduced the growth of tumor xenografts. Our studies directly demonstrate that repeat elements can acquire enhancer functions in cancer and become critical components of oncogenic gene regulation programs.

2018-07-30 | GSE106915 | GEO

Epigenome editing of microsatellite repeat enhancers reveals specific regulatory functions and tumor dependencies [ChIP-Seq]

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Epigenome editing of microsatellite repeat enhancers reveals specific regulatory functions and tumor dependencies

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

2018-07-30 | GSE106925 | GEO

Epigenome editing of microsatellite repeats defines tumor-specific enhancer functions and dependencies.

Project description:Various types of repetitive sequences are dysregulated in cancer. In Ewing sarcoma, the oncogenic fusion protein EWS-FLI1 induces chromatin features typical of active enhancers at GGAA microsatellite repeats, but the function of these sites has not been directly demonstrated. Here, by combining nascent transcription profiling with epigenome editing, we found that a subset of GGAA microsatellite repeats is transcriptionally active in Ewing sarcoma and that silencing individual repeats abolishes local nascent transcription and leads to markedly reduced expression of putative target genes. Epigenome silencing of these repeat sites does not affect gene expression in unrelated cells, can prevent the induction of gene expression by EWS-FLI1, and, in the case of a GGAA repeat that controls SOX2 expression from a distance of 470 kb, is sufficient to impair the growth of Ewing sarcoma xenografts. Using an experimental approach that is broadly applicable to testing different types of repetitive genomic elements, our study directly demonstrates that specific repeat microsatellites can have critical gene regulation functions in cancer and thus represent tumor-specific vulnerabilities that may be exploited to develop new therapies.

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ETV6 Deficiency and Microsatellite Enhancers Drive Transcriptional Dysregulation in B-Lymphoblastic Leukemia: RNA-Seq

Project description:Distal enhancers play critical roles in sustaining oncogenic gene expression programs. We obtained ATAC-Seq data and ChIP-Seq data using antibodies against the H3K27ac histone mark, transcription factors ERG and ETV6, and input chromatin from B-ALL cell lines and comparator B-cell cancer cell lines, including B-ALL with biallelic ETV6 inactivation, ETV6-RUNX1, and intact ETV6. We identify aberrant enhancer-like activation of GGAA tandem repeats as a characteristic feature of B-cell acute lymphoblastic leukemia (B-ALL) with genetic defects of the ETV6 transcriptional repressor, including ETV6-RUNX1+ and ETV6-null B-ALL. We show that GGAA repeat enhancers are direct activators of previously identified ETV6-RUNX1+ B-ALL “signature” genes, including likely oncogenic drivers. When restored to ETV6-deficient B-ALL cells, ETV6 directly binds to GGAA repeat enhancers, represses their acetylation, downregulates adjacent genes, and inhibits B-ALL growth. In ETV6-deficient B-ALL cells, we find that the ETS transcription factor ERG directly binds to GGAA microsatellite enhancers and is required for sustained activation of many repeat enhancer-activated genes. Together, our findings reveal a novel epigenetic gatekeeper function of the ETV6 tumor suppressor gene and establish microsatellite enhancers as a key mechanism underlying the unique gene expression program of ETV6-RUNX1+ B-ALL.

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ETV6 Deficiency and Microsatellite Enhancers Drive Transcriptional Dysregulation in B-Lymphoblastic Leukemia: ChIP-Seq data

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ETV6 Deficiency and Microsatellite Enhancers Drive Transcriptional Dysregulation in B-Lymphoblastic Leukemia: ATAC-Seq data

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Impeding transcription of expanded microsatellite repeats by deactivated Cas9

Project description:Transcription of expanded microsatellite repeats is associated with multiple human diseases, including myotonic dystrophy, Fuchs’ endothelial corneal dystrophy, and C9orf72-ALS/FTD. Eliminating or reducing production of RNA and proteins arising from these expanded loci holds therapeutic benefit. Here, we tested the hypothesis that a deactivated form of the Cas9 enzyme impedes transcription across expanded microsatellites. We observed a repeat length-, PAM-, and strand-dependent reduction in the abundance of repeat-containing RNAs upon targeting dCas9 directly to repeat sequences. Aberrant splicing patterns were rescued in DM1 cells, and production of RAN peptides characteristic of DM1, DM2, and C9orf72-ALS/FTD cells was drastically decreased. Systemic delivery of dCas9/gRNA by adeno-associated virus led to reductions in pathological RNA foci, rescue of chloride channel 1 protein expression, and decreased myotonia. These observations suggest that transcription of microsatellite repeat-containing RNAs is more sensitive to perturbation than transcription of other RNAs, indicating potentially viable strategies for therapeutic intervention.

2017-09-20 | GSE103997 | GEO

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