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Identification of endothelial gene regulatory elements during cardiopharyngeal lineage differentiation [ATAC-seq]

ABSTRACT: Endothelial cells (EC) differentiate from multiple sources during embryonic development, including the cardiopharyngeal mesoderm, which gives rise to multiple tissues including the cardiac and branchiomeric muscle. Here, we have used a cardiogenic mesoderm cell differentiation model that also activates an endothelial transcription program. Comparing our chromatin remodeling data with publicly available single-cell RNA-seq data from mouse embryos, we derived a list of over 100 putative regulatory elements activated in EC marker genes. We applied a machine-learning strategy trained with validate enhancers to predict the probability of these sequences to function as enhancers. The computational assay returned over 50% of these sequences to be likely enhancers, some of which previously reported. In addition, using genetic and epigenetic perturbations of some of these elements, we established their requirement for gene expression during endothelial differentiation. Finally, we used the integration of multiple data sources and computational tools to search for transcriptional factor binding motifs related to endothelial cell fate specification. We found motifs of GATA, ETS, and FOS/AP-1 factors as the most significantly enriched in these sequences. Overall, our approach has been efficient in the identification of novel EC regulatory sequences with high likelihood to be enhancers, and validated a subset of them. Motif analyses revealed that the core EC transcription factors GATA/ETS/FOS is a likely driver of EC differentiation in cardiopharyngeal mesoderm.

ORGANISM(S): Mus musculus

PROVIDER: GSE235650 | GEO | 2024/01/26

REPOSITORIES: GEO

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Project description:Dynamic gene expression programs determine multipotent cell states and fate choices during development. Multipotent progenitors for cardiomyocytes and branchiomeric head muscles populate the pharyngeal mesoderm of vertebrate embryos, but the mechanisms underlying cardiopharyngeal multipotency and heart vs. head muscle fate choices remain elusive. The tunicate Ciona emerged as a simple chordate model to study cardiopharyngeal development with unprecedented spatio-temporal resolution. We analyzed the transcriptome of single cardiopharyngeal lineage cells isolated at successive time points encompassing the transitions from multipotent progenitors to distinct first and second heart, and pharyngeal muscle precursors. We reconstructed the three cardiopharyngeal developmental trajectories, and characterized gene expression dynamics and regulatory states underlying each fate choice. Experimental perturbations and bulk transcriptome analyses revealed that ongoing FGF/MAPK signaling maintains cardiopharyngeal multipotency and promotes the pharyngeal muscle fate, whereas signal termination permits the deployment of a full pan-cardiac program and heart fate specification. We identified the Dach1/2 homolog as a novel evolutionarily conserved second-heart-field-specific factor and demonstrate, through lineage tracing and CRISPR/Cas9 perturbations, that it operates downstream of Tbx1/10 to actively suppress the first heart lineage program. This data indicates that the regulatory state of multipotent cardiopharyngeal progenitors determines the first vs. second heart lineage choice, and that Tbx1/10 acts as a bona fide regulator of cardiopharyngeal multi potency. We performed bulk RNAseq to profile the FACS purified Ciona Robusta Truck Ventral Cells (TVCs) with FGF-MAPK perturbation conditions to address the question- What is the role of FGF signaling pathway during early cardiopharyngeal specification. we performed bulk RNA sequencing of FACS-purified cardiopharyngeal lineage cells isolated from embryos and larvae expressing either a dominant negative form the fibroblast growth factor receptor (dnFGFR), or a constitutively active form of M-Ras (caM-Ras), the sole Ras homolog in Ciona, under the control of TVC-specific enhancers.

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Identification of endothelial gene regulatory elements during cardiopharyngeal lineage differentiation [ATAC-seq]

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