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

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

PROVIDER: PRJNA776847 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16677000_1.fastq.gz	Fastqsanger.gz
	SRR16677000_2.fastq.gz	Fastqsanger.gz
	SRR16677001_1.fastq.gz	Fastqsanger.gz
	SRR16677001_2.fastq.gz	Fastqsanger.gz
	SRR16677002_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

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.

2022-10-23 | GSE186936 | GEO

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

2022-10-23 | GSE186938 | GEO

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

2022-10-23 | GSE186941 | GEO

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

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

| PRJNA776851 | ENA

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

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

| PRJNA776845 | ENA

ETV6 Deficiency Unlocks ERG-Dependent Microsatellite Enhancers to Drive Aberrant Gene Activation in B-Lymphoblastic Leukemia

Project description:ETV6 Deficiency Unlocks ERG-Dependent Microsatellite Enhancers to Drive Aberrant Gene Activation in B-Lymphoblastic Leukemia

| PRJNA776849 | ENA

ETV6 Deficiency Unlocks ERG-Dependent Microsatellite Enhancers to Drive Aberrant Gene Activation in B-Lymphoblastic Leukemia.

Project description:Distal enhancers play critical roles in sustaining oncogenic gene-expression programs. 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+/- like B-ALL "signature" genes, including the likely leukemogenic driver EPOR. 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 repeat enhancer-activated genes. Together, our findings reveal an 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+/- like B-ALL.SignificanceWe find a unifying mechanism underlying a leukemia subtype-defining gene-expression signature that relies on repetitive elements with poor conservation between humans and rodents. The ability of ETV6 to antagonize promiscuous, nonphysiologic ERG activity may shed light on other roles of these key regulators in hematolymphoid development and human disease. See related commentary by Mercher, p. 2. This article is highlighted in the In This Issue feature, p. 1.

| S-EPMC9820540 | biostudies-literature

Illumina and Affymetrix SNP-array data for 2 ETV6/RUNX1-positive Acute Lymphoblastic Leukemia samples and corresponding normal samples

Project description:This SuperSeries is composed of the following subset Series: GSE25102: Illumina SNP-array data for 2 ETV6/RUNX1-positive Acute Lymphoblastic Leukemia samples and corresponding normal samples GSE25116: Affymetrix SNP-array data for 2 ETV6/RUNX1-positive Acute Lymphoblastic Leukemia samples and corresponding normal samples Refer to individual Series

2012-07-02 | E-GEOD-25117 | biostudies-arrayexpress

CLIC5: a novel ETV6 target gene in childhood acute lymphoblastic leukemia

Project description:Background: The most common rearrangement in childhood precursor B-cell acute lymphoblastic leukemia (pre-B ALL) is the t(12;21)(p13;q22) translocation resulting in the ETV6-AML1 fusion gene. A frequent concomitant event is the loss of the residual ETV6 allele suggesting a critical role for the ETV6 transcriptional repressor in the etiology of pre-B ALL. However, the precise mechanism through which loss of functional ETV6 contributes to disease pathogenesis is still unclear Results: To investigate the impact of ETV6 loss on the transcriptional network and identify new transcriptional targets of ETV6, we used whole transcriptome analysis of both pre-B leukemic cell lines and pre-B ALL patients combined with chromatin immunoprecipitation. Using this integrative approach, we identified 4 novel direct ETV6 target genes: CLIC5, BIRC7, ANGPTL2 and WBP1L. To further evaluate the role of chloride intracellular channel protein CLIC5 in leukemogenesis, we generated cell lines overexpressing CLIC5 and demonstrated an increased resistance to hydrogen peroxide-induced apoptosis. We further described the implications of CLIC5’s ion channel activity in lysosomal-mediated cell death, possibly by modulating the function of transferrin receptor with which it co-localizes intracellularly. Conclusion: For the first time, we showed that loss of ETV6 leads to significant overexpression of CLIC5, which in turn leads to decreased lysosome-mediated apoptosis. Our data suggest that heightened CLIC5 activity could promote a permissive environment for oxidative-stress induced DNA damage accumulation and thereby contribute to leukemogenesis.

2016-03-18 | GSE79373 | GEO

ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation

Project description:we report a synthetic lethality of ETV6 and EWS-FLI1 in ewing sarcome that is imposed by ETV6 antagonize EWS-FLI1 from particular GGAA microsatellite sites

2022-10-18 | GSE189418 | GEO

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