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

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

PROVIDER: PRJNA776849 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16677000_1.fastq.gz	Fastqsanger.gz
	SRR16677000_2.fastq.gz	Fastqsanger.gz
	SRR16677100_1.fastq.gz	Fastqsanger.gz
	SRR16677100_2.fastq.gz	Fastqsanger.gz
	SRR16677001_1.fastq.gz	Fastqsanger.gz

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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.

2022-10-23 | GSE186936 | GEO

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

2022-10-23 | GSE186938 | GEO

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

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

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

2022-10-22 | GSE186942 | 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

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

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

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Identification of ETV6 bound protein by affinity purification of ETV6-HA fusion protein in REH cells

Project description:To determine the protein partners of ETV6, we expressed ETV6 and HA-tagged ETV6 in Reh pre-B leukemic cells. Anti-HA magnetic beads were used for affinity purification of ETV6-HA (and ETV6 control) from the nuclear and cytoplasmic fraction. Following purification on-beads digest and LC-MS/MS experiments were performed at the Proteomics platform of the CHU de Quebec Research Center, Quebec, Canada.

2022-01-26 | PXD031001 | Pride

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 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