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

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

PROVIDER: PRJNA474192 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7248470_1.fastq.gz	Fastqsanger.gz
	SRR7248470_2.fastq.gz	Fastqsanger.gz
	SRR7248480_1.fastq.gz	Fastqsanger.gz
	SRR7248480_2.fastq.gz	Fastqsanger.gz
	SRR7248471_1.fastq.gz	Fastqsanger.gz

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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.

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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

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Project description:The ETV6/RUNX1 fusion gene, present in 25% of B-lineage childhood acute lymphoblastic leukemia (ALL), is thought to represent an initiating event, which requires additional genetic changes for leukemia development. To identify additional genetic alterations, 24 ETV6/RUNX1-positive ALLs were analyzed using 500K single nucleotide polymorphism arrays. The results were combined with previously published data sets, allowing us to ascertain genomic copy number aberrations (CNAs) in 164 cases. In total, 45 recurrent CNAs were identified with an average number of 3.5 recurrent changes per case (range 0-13). Twenty-six percent of cases displayed a set of recurrent CNAs identical to that of other cases in the data set. The majority (74%), however, displayed a unique pattern of recurrent CNAs, indicating a large heterogeneity within this ALL subtype. As previously demonstrated, alterations targeting genes involved in B-cell development were common (present in 28% of cases). However, the combined analysis also identified alterations affecting nuclear hormone response (24%) to be a characteristic feature of ETV6/RUNX1-positive ALL. Studying the correlation pattern of the CNAs allowed us to highlight significant positive and negative correlations between specific aberrations. Furthermore, oncogenetic tree models identified ETV6, CDKN2A/B, PAX5, del(6q), and +16 as possible early events in the leukemogenic process. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from 23 leukemic bone marrow samples and one ETV6/RUNX1-positive cell line.

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Etv6 activates vegfa expression through positive and negative transcriptional regulatory networks in Xenopus embryos.

Project description:VEGFA signaling controls physiological and pathological angiogenesis and hematopoiesis. Although many context-dependent signaling pathways downstream of VEGFA have been uncovered, vegfa transcriptional regulation in vivo remains unclear. Here, we show that the ETS transcription factor, Etv6, positively regulates vegfa expression during Xenopus blood stem cell development through multiple transcriptional inputs. In agreement with its established repressive functions, Etv6 directly inhibits expression of the repressor foxo3, to prevent Foxo3 from binding to and repressing the vegfa promoter. Etv6 also directly activates expression of the activator klf4; reflecting a genome-wide paucity in ETS-binding motifs in Etv6 genomic targets, Klf4 then recruits Etv6 to the vegfa promoter to activate its expression. These two mechanisms (double negative gate and feed-forward loop) are classic features of gene regulatory networks specifying cell fates. Thus, Etv6's dual function, as a transcriptional repressor and activator, controls a major signaling pathway involved in endothelial and blood development in vivo.

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