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ETV2 Upregulation Marks the Specification of Early Cardiomyocytes and Endothelial Cells During Co-differentiation

ABSTRACT: The ability to differentiate human induced pluripotent stem cells (hiPSCs) efficiently into defined cardiac lineages, such as cardiomyocytes and cardiac endothelial cells, is crucial to study human heart development and model cardiovascular diseases in vitro. The mechanisms underlying the specification of these cell types during human development are not well-understood which limits fine-tuning and broader application of cardiac model systems. Here, we used the expression of ETV2, a master regulator of hematoendothelial specification in mice, to identify functionally distinct subpopulations during the co-differentiation of endothelial cells and cardiomyocytes from hiPSCs. Targeted analysis of single-cell RNA sequencing data revealed differential ETV2 dynamics in the two lineages. A newly created fluorescent reporter line allowed us to identify early lineage-predisposed states and show that a transient ETV2-high state initiates the specification of endothelial cells. We further demonstrated, unexpectedly, that functional cardiomyocytes can originate from progenitors expressing ETV2 at a low level. Our study thus sheds light on the in vitro differentiation dynamics of two important cardiac lineages.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157954 | GEO | 2023/01/20

REPOSITORIES: GEO

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ETV2 upregulation marks the specification of early cardiomyocytes and endothelial cells during co-differentiation

Project description:The ability to differentiate human induced pluripotent stem cells (hiPSCs) efficiently into defined cardiac lineages, such as cardiomyocytes and cardiac endothelial cells, is crucial to study human heart development and model cardiovascular diseases in vitro. The mechanisms underlying the specification of these cell types during human development are not well-understood which limits fine-tuning and broader application of cardiac model systems. Here, we used the expression of ETV2, a master regulator of hematoendothelial specification in mice, to identify functionally distinct subpopulations during the co-differentiation of endothelial cells and cardiomyocytes from hiPSCs. Targeted analysis of single-cell RNA sequencing data revealed differential ETV2 dynamics in the two lineages. A newly created fluorescent reporter line allowed us to identify early lineage-predisposed states and show that a transient ETV2-high state initiates the specification of endothelial cells. We further demonstrated, unexpectedly, that functional cardiomyocytes can originate from progenitors expressing ETV2 at a low level. Our study thus sheds light on the in vitro differentiation dynamics of two important cardiac lineages.

2023-01-20 | GSE202901 | GEO

ETV2 primes hematoendothelial gene enhancers prior to hematoendothelial fate commitment

Project description:The lineage-determining transcription factor ETV2 is necessary and sufficient for hematoendothelial fate commitment. We investigated how ETV2-driven gene regulatory networks promote hematoendothelial fate commitment. We resolved the sequential determination steps of hematoendothelial versus cardiac differentiation from mouse embryonic stem cells. Etv2 was strongly induced and bound to the enhancers of hematoendothelial genes in a common cardiomyocyte-hematoendothelial mesoderm progenitor. However, only Etv2 itself and Tal1, not other ETV2-bound genes, were induced. Despite ETV2 genomic binding and Etv2 and Tal1 expression, cardiomyogenic fate potential was maintained. A second wave of ETV2-bound target genes was up-regulated during the transition from the common cardiomyocyte-hematoendothelial progenitor to the committed hematoendothelial population. A third wave of ETV-bound genes were subsequently expressed in the committed hematoendothelial population for sub-lineage differentiation. The shift from ETV2 binding to productive transcription, not ETV2 binding to target gene enhancers, drove hematoendothelial fate commitment. This work identifies mechanistic phases of ETV2-dependent gene expression that distinguish hematoendothelial specification, commitment, and differentiation.

2023-06-16 | GSE136692 | GEO

NOMeseq analysis of Etv2 induced MEF reprogramming

Project description:The vasculature is an essential organ for the delivery of blood and oxygen to all tissues of the body and thus relevant to the treatment of ischemic diseases, injury-induced regeneration, and solid tumor growth. Therefore, the definition of pioneer factors and regulatory pathways that govern the specification and differentiation of endothelial progenitors will serve as a platform for targeted therapies to promote cardiovascular regeneration and treatment of solid organ tumors. Previously, we demonstrated that ETV2 was an essential transcription factor for the development of cardiac, endothelial and hematopoietic lineages. Here, we report that ETV2 functions as a novel pioneer factor that relaxes closed chromatin and regulates endothelial development. By comparing engineered embryonic stem cell differentiation and reprogramming models with single cell RNA-seq, ATAC-seq and ChIP-seq techniques, we demonstrated that ETV2 was able to bind nucleosomal DNA and function as a pioneer factor independent of the cellular context. We determined that ETV2 executes a pioneering role by recruiting BRG1 to remodel chromatin around endothelial genes and help maintain an open configuration. ETV2 chromatin binding also resulted in increased H3K27ac deposition. Collectively, these results will serve as a platform for the development of therapeutic initiatives directed towards cardiovascular and oncological diseases.

2022-10-04 | GSE185681 | GEO

Bulk RNA-seq analysis of Etv2 induced EB differentiation.

2022-01-12 | GSE185682 | GEO

Single cell RNA-seq analysis of Etv2 induced MEFs reprogramming.

2022-01-12 | GSE185683 | GEO

ETV2/ER71 regulates hematovascular lineage generation and vascularization through an H3K9 demethylase, KDM4A

Project description:ETV2/ER71, an ETS transcription factor, is critical for hematopoiesis and vascular development. However, knowledge on the molecular mechanisms behind ETV2-mediated gene transcription is limited. Here, we show that ETV2 together with KDM4A, an H3K9 demethylase, regulates hematopoietic and endothelial genes. Etv2-/- mouse embryonic stem cells (mESCs), which fail to generate hematopoietic and endothelial cells, showed enhanced levels of H3K9me3 on hematopoietic and endothelial genes. ETV2 interacts with KDM4A and the ETV2-mediated transcriptional activation of hematopoietic and endothelial genes is dependent on KDM4A histone demethylase activity. ETV2 and KDM4A co-occupy the transcription regulatory regions of genes whose expression is directly regulated by ETV2. Mice lacking Kdm4a and Etv2 in endothelial cells (Cdh5Cre;Kdm4af/f;Etv2f/f) displayed a more severe defect in perfusion recovery and neovascularization compared with Cdh5Cre;Kdm4af/f, Cdh5Cre;Etv2f/f mice and controls. Collectively, we demonstrated that ETV2 interacts with KDM4A and that this interaction is critical for FLK1+ cell generation, differentiation into the downstream lineages, and vascular regeneration.

2024-12-10 | GSE251753 | GEO

Gene expression analysis of inducible ES cells overexpressing Etv2 (induced for 12 hours at day 3 of differentiation)

Project description:During embryogenesis, the endothelial and the hematopoietic lineages first appear during gastrulation in the blood island of the yolk sac. We have previously reported that an Ets variant gene 2 (Etv2/ER71) mutant embryo lacks hematopoietic and endothelial lineages, however, the precise roles of Etv2 in yolk sac development remains unclear. We carried out a transcriptome analysis using an ES cell line that can inducibly express Etv2. Cells were induced for 12 hours at day 3 of differentiation. An ES cell line (dervied from mouse of background strain 129P2/Ola) with a doxycycline inducible expression casette of Etv2 (ER71 A2Lox.cre) was differentiated in hanging drops. At 3 days of differentiation, cells were treated with doxycycline for 12 hours, and subsequently Flk1(+) cells were sorted. Experiment was done in triplicate and untreated cells were used for control.

2012-07-03 | E-GEOD-37658 | biostudies-arrayexpress

Gene expression analysis of inducible ES cells overexpressing Etv2 (induced for 12 hours at day 3 of differentiation)

2012-07-04 | GSE37658 | GEO

Comparison of Flk-1+/Etv2- vs Flk-1+/Etv2+ populations

Project description:Screening for genes up in Etv2+ cells within Flk-1+ ES derived mesoderm Microarray analysis performed to screen for the candidate genes regulated by Etv2. Differentiated Flk-1+ mesoderm can be devided into Etv2+ or-. Etv2+ cells are assumed to be committed to hemato/endothelial cells. Comparison of two populations can reveal genes relevant in this commitment. Extract RNA from sorted Flk-1+/Etv2- vs Flk-1+/Etv2+ populations.Etv2-Venus KI ES cells were differentiated on OP9 for 4-5 days and Flk-1+ population was separated into Etv2-Venus+ or- cells. Total RNA was purified from each population for analysis.

2011-08-30 | E-GEOD-31743 | biostudies-arrayexpress

Etv2-mediated hemangiogenic fate commitment of mesoderm

Project description:A comprehensive understanding of a lineage map and molecular mechanisms underlying lineage specification is fundamental to development. To this end, ETS transcription factor Etv2 functions as the master regulator of hematopoietic and endothelial cell formation. As such, Etv2 regulated hemangiogenesis provides an excellent model for assessing cell lineage specification. Herein, we generated several reporter embryonic stem (ES) cell lines to map developmental route pertaining to hemangiogenesis. We performed transcriptome analysis and high throughput CRISPR screening to further delineate molecular mechanisms regulating hemangiogenic lineage specification. We show a distinct lineage map of hemangiogenesis, in which hemangiogenic fate is specified not simply by the onset of Etv2 expression, but in a threshold-dependent manner. Importantly, VEGF-FLK1 signaling is necessary for efficiently achieving ETV2-threshold. Moreover, we find forkhead transcription factor Foxh1 to be required for FLK1 mesoderm formation. These studies provide a roadmap in hematopoietic and vascular cell generation and applications in regenerative medicine.

2017-08-01 | GSE85641 | GEO

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