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Genome-wide strategies reveal downstream target genes of Npas4l associated with cardiovascular development in zebrafish [ATAC-Seq]

ABSTRACT: The development of a vascular network is essential to nourish tissues and sustain organ function throughout life. Endothelial cells (ECs) are the building blocks of blood vessels, yet our understanding of EC specification in vertebrates remains incomplete. cloche/npas4l mutants have broadly been used as an avascular model in zebrafish, but little is known about the molecular mechanism of action of Npas4l. Here, to identify the direct and indirect target genes of this transcription factor, we combined complementary genome-wide approaches, including transcriptome analyses and chromatin immunoprecipitation (ChIP). The cross-analysis of these datasets indicate that Npas4l functions as a master regulator by directly inducing a wave of transcription factor genes crucial for hematoendothelial specification in vertebrates, including etv2, tal1, and lmo2. We identified additional target genes acting downstream of npas4l and investigated the function of a subset of them using CRISPR/Cas9 technology. Phenotypic characterization of tspan18b mutants reveals a novel role for tspan18b in developmental angiogenesis, confirming the reliability of the datasets generated. Collectively, these data represent a useful resource for future studies aimed to investigate novel genes with a potential role in vascular development and EC fate determination in vertebrates.

ORGANISM(S): Danio rerio

PROVIDER: GSE130196 | GEO | 2019/05/21

REPOSITORIES: GEO

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Genome-wide strategies reveal downstream target genes of Npas4l associated with vascular development in zebrafish [ChIP-Seq]

Project description:The development of a vascular network is essential to nourish tissues and sustain organ function throughout life. Endothelial cells (ECs) are the building blocks of blood vessels, yet our understanding of EC specification in vertebrates remains incomplete. cloche/npas4l mutants have broadly been used as an avascular model in zebrafish, but little is known about the molecular mechanism of action of Npas4l. Here, to identify the direct and indirect target genes of this transcription factor, we combined complementary genome-wide approaches, including transcriptome analyses and chromatin immunoprecipitation (ChIP). The cross-analysis of these datasets indicate that Npas4l functions as a master regulator by directly inducing a wave of transcription factor genes crucial for hematoendothelial specification in vertebrates, including etv2, tal1, and lmo2. We identified additional target genes acting downstream of npas4l and investigated the function of a subset of them using CRISPR/Cas9 technology. Phenotypic characterization of tspan18b mutants reveals a novel role for tspan18b in developmental angiogenesis, confirming the reliability of the datasets generated. Collectively, these data represent a useful resource for future studies aimed to investigate novel genes with a potential role in vascular development and EC fate determination in vertebrates.

2019-05-21 | GSE130198 | GEO

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Genome-wide strategies reveal downstream target genes of Npas4l associated with cardiovascular development in zebrafish [RNA-Seq 1]

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Project description:Embryonic cells including endothelial progenitors undergo extensive migration and differentiation events; however, whether and how these processes are interrelated remains unclear. The transcription factor Npas4l is necessary for endothelial specification in zebrafish by inducing the expression of the transcription factor genes etsrp, tal1 and lmo2. We generated a knock-in reporter in the npas4l locus to visualize endothelial progenitors and their derivatives in wild-type and mutant embryos. We find that in npas4l mutants, npas4l reporter expressing cells do not migrate to the midline and instead contribute to skeletal muscle and pronephric tubules. Investigating the Npas4l transcriptional effectors, we find that npas4l reporter expressing cells in tal1 mutants fail to migrate while those in etsrp mutants migrate but fail to differentiate. In lmo2 mutants, npas4l reporter expressing cells migrate and differentiate, but many express pronephric tubule markers. Altogether, these data reveal the complex regulation of endothelial progenitor migration, differentiation and fate restriction.

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Endothelial progenitor migration and differentiation is regulated by distinct transcriptional effectors of Cloche/Npas4l

Project description:Endothelial progenitor migration and differentiation is regulated by distinct transcriptional effectors of Cloche/Npas4l

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kdrl:eGFP+ ECs isolated from wildtype, etsrp-null, npas4l-null, and sox32-null zebrafish embryos

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2023-06-16 | GSE136692 | GEO

Multi-modal characterization of chromatin architecture from 24 hpf whole zebrafish embryos

Project description:DNA accessibility of cis regulatory elements (CREs) dictates transcriptional activity and drives cell differentiation during development. To obtain a more comprehensive view of CRE dynamics, we applied single-cell combinatorial indexing ATAC-seq (sci-ATAC-seq) to whole 24hpf stage zebrafish embryos thereby measuring DNA accessibility in ~23,000 single cells. We developed two solutions to computational challenges in analyzing single-cell accessibility maps: 1) selection of informative genome segments, and 2) genome-wide classification of both cell-type-specific and multi-cell-type accessibility dynamics. We validated the sci-ATAC-seq results with bulk measurements for histone post-translational modifications and 3D genome organization, recovering known relationships between chromatin modalities and providing additional regulatory classifications. Furthermore, we applied sci-ATAC-seq to cloche/npas4l mutant embryos which revealed known and novel cellular roles for the hemato-vascular transcriptional master regulator, and suggested an intricate network regulating its expression. These data and their extensive analysis constitute a valuable developmental, molecular, and computational resource for future studies.

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GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis (3 of 3)

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