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Etv6-dependent positive and negative gene regulatory network controls vegfa expression in vivo [RNA-seq]

ABSTRACT: VEGFA signaling is crucial for physiological and pathological angiogenesis and hematopoiesis. Although many context-dependent signaling pathways downstream of VegfA have been uncovered, vegfa transcriptional regulation in vivo is unclear. Here, we show that ETS transcription factor Etv6 positively regulates vegfa expression during blood stem cell development through multiple transcriptional inputs. In agreement with its established repressive functions, Etv6 directly inhibits expression of vegfa repressor foxo3. Surprisingly, it also directly activates expression of vegfa activator klf4. Finally, it indirectly binds to vegfa promoter by the recruiment of Klf4. Thus, our work uncovers a dual function for Etv6, as both a transcriptional repressor and activator, in controlling a major signaling pathway.

ORGANISM(S): Xenopus laevis

PROVIDER: GSE115220 | GEO | 2019/01/16

REPOSITORIES: GEO

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Etv6-dependent positive and negative gene regulatory network controls vegfa expression in vivo [ChIP-seq]

Project description:VEGFA signaling is crucial for physiological and pathological angiogenesis and hematopoiesis. Although many context-dependent signaling pathways downstream of VegfA have been uncovered, vegfa transcriptional regulation in vivo is unclear. Here, we show that ETS transcription factor Etv6 positively regulates vegfa expression during blood stem cell development through multiple transcriptional inputs. In agreement with its established repressive functions, Etv6 directly inhibits expression of vegfa repressor foxo3. Surprisingly, it also directly activates expression of vegfa activator klf4. Finally, it indirectly binds to vegfa promoter by the recruiment of Klf4. Thus, our work uncovers a dual function for Etv6, as both a transcriptional repressor and activator, in controlling a major signaling pathway.

2019-01-16 | GSE115224 | GEO

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

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2022-10-23 | GSE186936 | GEO

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: 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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Etv6-dependent positive and negative gene regulatory network controls vegfa expression in vivo

Project description:Etv6-dependent positive and negative gene regulatory network controls vegfa expression in vivo

| PRJNA474200 | ENA

Genome wide mapping of ETV6 binding sites in pre-B leukemic cells

Project description:Background: Genetic alterations in the transcriptional repressor ETV6 are associated with hematological malignancies. Notably, the t(12;21) translocation leading to an ETV6-AML1 fusion gene is the most common genetic alteration found in childhood acute lymphoblastic leukemia. Moreover, most of these patients also lack ETV6 expression, suggesting a tumor suppressor function. Results: To gain insights on ETV6 DNA-binding specificity and genome wide transcriptional regulation capacities, we performed chromatin immunoprecipitation experiments coupled to deep sequencing in a t(12;21)-positive pre-B leukemic cell line. This strategy led to high quality ETV6-bound regions. ETV6 binding is mostly cell type-specific as only few regions are shared with other blood cell subtypes. Peaks localization and motif enrichment analyses revealed a unique binding profile that is associated with the presence of the ETV6-AML1 fusion product. Conclusions: We described the first ETV6 binding map in the t(12;21) background. This study highlighted the complex and unique interplay between ETV6 and ETV6-AML1 and underscored the highly regulated mechanisms of ETV6 binding. ETV6 inactivation observed in this context could induce specific transcriptional changes promoting leukemic transformation.

2017-11-15 | GSE102785 | GEO

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-dependent positive and negative gene regulatory network controls vegfa expression in vivo [RNA-seq]

Project description:Etv6-dependent positive and negative gene regulatory network controls vegfa expression in vivo [RNA-seq]

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Etv6-dependent positive and negative gene regulatory network controls vegfa expression in vivo [ChIP-seq]

Project description:Etv6-dependent positive and negative gene regulatory network controls vegfa expression in vivo [ChIP-seq]

| PRJNA474199 | ENA