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Comprehensive Mapping of Transcriptionally-active Enhancers During Murine Cardiogenesis at Single Cell Resolution

ABSTRACT: An in-depth understanding of the complex mechanisms that orchestrate normal embryonic heart development is required to disambiguate the origin of congenital heart disease. However, the epigenetic landscapes governing cell type-specific gene expression patterns during heart development at single cell resolution has yet to be revealed. Here we use simultaneous single cell RNA and assay for transposase accessible chromatin sequencing to construct a comprehensive multimodal map of embryonic murine heart development, profiling cell type- and timepoint-specific epigenetic regulatory elements as well as their gene targets. Furthermore, we compare these regulatory elements with published GWAS hits to map variants implicated in key developmental processes and clinical phenotypes to enhancers for genes that are actively transcribed during cardiac development. Taken together, our work provides a rich resource for the broader scientific community that empowers future studies in heart development and disease and offers a simple computational framework for integrating and profiling multiomic data in single cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE244783 | GEO | 2025/10/31

REPOSITORIES: GEO

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Project description:Mammalian heart development is built on highly conserved molecular mechanisms with polygenetic perturbations resulting in a spectrum of congenital heart diseases (CHD). However, the transcriptional landscape of cardiogenic ontogeny that regulates proper cardiogenesis remains largely based on candidate-gene approaches. Herein, we designed a time-course transcriptome analysis to investigate the genome-wide expression profile of innate murine cardiogenesis ranging from embryonic stem cells to adult cardiac structures. This comprehensive analysis generated temporal and spatial expression profiles, prioritized stage-specific gene functions, and mapped the dynamic transcriptome of cardiogenesis to curated pathways. Reconciling the bioinformatics of the congenital heart disease interactome, we deconstructed disease-centric regulatory networks encoded within this cardiogenic atlas to reveal stage-specific developmental disturbances clustered on epithelial-to-mesenchymal transition (EMT), BMP regulation, NF-AT signaling, TGFb-dependent induction, and Notch signaling. Therefore, this cardiogenic transcriptional landscape defines the time-dependent expression of cardiac ontogeny and prioritizes regulatory networks at the interface between health and disease. To interrogate the temporal and spatial expression profiles across the entire genome during mammalian heart development, we designed a time-course microarray experiment using the mouse model at defined stages of cardiogenesis, starting with embryonic stem cells (ESC, R1 stem cell line), early embryonic developmental stages: E7.5 whole embryos, E8.5 heart tubes, left and right ventricle tissues at E9.5, E12.5, E14.5, E18.5 to 3 days after birth (D3) and adult heart (Figure 1A). At each time point, microarray experiments were performed on triplicate biological samples. Starting at E9.5, tissue samples from left ventricles (LV) and right ventricles (RV) were microdissected for RNA purification and microarray analysis to determine spatially differential gene expression between LV and RV during heart development.

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Comprehensive Mapping of Transcriptionally-active Enhancers During Murine Cardiogenesis at Single Cell Resolution

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