A Linc1405/Eomes Complex Promotes Cardiac Mesoderm Specification and Cardiogenesis
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ABSTRACT:
PROVIDER: PRJNA435989 | ENA |
REPOSITORIES: ENA
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Project description:Large intergenic non-coding RNAs (lincRNAs) play widespread roles in epigenetic regulation during multiple differentiation processes, but little is known about their mode of action in cardiac differentiation. Here, we identified the key roles of a lincRNA, termed linc1405, in modulating the core network of cardiac differentiation by functionally interacting with Eomes. Chromatin- and RNA- immunoprecipitation assays showed that exon2 of linc1405 physically mediates a complex consisting of Eomes, Trithorax group (TrxG) subunit WDR5, and histone acetyltransferase GCN5 binding at the enhancer region of Mesp1 gene and activates its expression during cardiac mesoderm specification of embryonic stem cells. Importantly, linc1405 co-localizes with Eomes, WDR5, and GCN5 at the primitive streak and linc1405 depletion impairs heart development and function in vivo. In summary, linc1405 mediates a Eomes/WDR5/GCN5 complex that contributes to cardiogenesis, highlighting the critical roles of lincRNA-based complexes in the epigenetic regulation of cardiogenesis in vitro and in vivo.
2018-02-27 | GSE111132 | GEO
Project description:Cardiac lineage specification in the mouse is controlled by TGFβ and WNT signaling. From fly to fish, BMP has been identified as an indispensable heart inducer. A detailed analysis of the role of Bmp4 and its effectors Smad1/5, however, was still missing. We show that Bmp4 induces cardiac mesoderm formation in murine embryonic stem cells in vitro. Bmp4 first activates Wnt3 and upregulates Nodal. pSmad1/5 and the WNT effector Tcf3 form a complex, and together with pSmad2/3 activate mesoderm enhancers and Eomes. They then cooperate with Eomes to consolidate the expression of many mesoderm factors, including T. Eomes and T form a positive feedback loop and open additional enhancers regulating early mesoderm genes, including the transcription factor Mesp1 establishing the cardiac mesoderm lineage. In parallel, the neural fate is suppressed. Our data confirm the pivotal role of Bmp4 in cardiac mesoderm formation in the mouse. We describe in detail the consecutive and cooperative actions of three signaling pathways, BMP, WNT and Nodal, and their effector transcription factors, during cardiac mesoderm specification.
2023-05-03 | GSE168580 | GEO
Project description:The Tbx factors Eomesodermin (Eomes) and Brachyury instruct endoderm and mesoderm specification. Both Tbx factors have common large overlap in chromatin binding sites, however their embryonic phenotypes of mutants largely differ. In this study, we delineate the distinct binding patterns and gene target sets of Eomes and Brachyury providing a molecular model of distinct fate specification programs.
2023-07-26 | GSE194192 | GEO
Project description:Self-organisation and coordinated morphogenesis of multiple cardiac lineages is essential for the development and function of the heart1-3. However, the absence of a human in vitro model that mimics the basic lineage architecture of the heart hinders research into developmental mechanisms and congenital defects4. Here, we describe the establishment of a reliable, lineage-controlled and high-throughput cardiac organoid platform. We show that cardiac mesoderm derived from human pluripotent stem cells robustly self-organises and differentiates into cardiomyocytes forming a cavity. Co-differentiation of cardiomyocytes and endothelial cells from cardiac mesoderm within these structures is required to form a separate endothelial layer. As in vivo, the epicardium engulfs these cardiac organoids, migrates into the cardiomyocyte layer and differentiates. We use this model to demonstrate that cardiac cavity formation is controlled by a mesodermal WNT-BMP signalling axis. Disruption of one of the key BMP targets in cardiac mesoderm, the transcription factor HAND1, interferes with cavity formation, which is consistent with its role in early heart tube and left chamber development5. Thus, the cardiac organoid platform represents a powerful resource for the quantitative and mechanistic analysis of early human cardiogenesis and defects that are otherwise inaccessible. Beyond understanding congenital heart disease, cardiac organoids provide a foundation for future translational research into human cardiac disorders.
2021-05-18 | PXD018306 | Pride
Project description:Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization. Canalization is essential for stabilizing cell fate, but mechanisms underlying robust canalization are unclear. Here we show that the BRG1/BRM-associated factor (BAF) chromatin remodeling complex ATPase gene Brm safeguards cell identity during directed cardiogenesis of mouse embryonic stem cells. Despite establishment of well-differentiated precardiac mesoderm, Brm-null cells predominantly became neural precursors, violating germ layer assignment. Trajectory inference showed sudden acquisition of non-mesodermal identity in Brm-null cells, consistent with a new transition state referred to as a saddle-node bifurcation. Mechanistically, loss of Brm prevented de novo accessibility of cardiac enhancers while increasing expression of neurogenic factor POU3F1, preventing expression of neural suppressor REST, and disrupting composition of BRG1 complexes. Brm mutant identity switch was overcome by increasing BMP4 levels during mesoderm induction. Mathematical modeling supports all our observations. In the mouse embryo, Brm deletion exacerbated mesoderm-deleted Brg1 mutant phenotypes, severely compromising cardiogenesis, unmasking an in vivo role for Brm. Our results reveal Brm as a compensable safeguard of the fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory.
2021-11-03 | PXD026638 | Pride
Project description:During early development multiple progenitor populations contribute to the formation of the four-chambered heart and its diverse lineages. However, the underlying mechanisms that result in the specification of these progenitor populations are not yet fully understood. We have recently identified a population of cells that gives rise selectively to cardiovascular cells of the heart ventricles. Here, we have used this knowledge to isolate and profile subsets of cardiac mesoderm cells from the mouse embryo and have identified an enrichment for the Notch signaling pathway in ventricular cardiac mesoderm. Using the pluripotent stem cell differentiation system to investigate the role of Notch in a temporally controlled manner, we show that Notch induction increases cardiomyocyte differentiation efficiency. This is due to the enhanced specification of mesoderm to the cardiac lineage. Finally, our data suggests that Notch interacts with WNT signaling to enhance commitment to the cardiac lineage. Overall, our findings support the notion that key signaling events during early heart development are critical for proper lineage specification and segregation and provide additional detail into these processes in mouse and human cardiogenesis.
2023-01-07 | GSE143227 | GEO
Project description:During early development multiple progenitor populations contribute to the formation of the four-chambered heart and its diverse lineages. However, the underlying mechanisms that result in the specification of these progenitor populations are not yet fully understood. We have recently identified a population of cells that gives rise selectively to cardiovascular cells of the heart ventricles. Here, we have used this knowledge to isolate and profile subsets of cardiac mesoderm cells from the mouse embryo and have identified an enrichment for the Notch signaling pathway in ventricular cardiac mesoderm. Using the pluripotent stem cell differentiation system to investigate the role of Notch in a temporally controlled manner, we show that Notch induction increases cardiomyocyte differentiation efficiency. This is due to the enhanced specification of mesoderm to the cardiac lineage. Finally, our data suggests that Notch interacts with WNT signaling to enhance commitment to the cardiac lineage. Overall, our findings support the notion that key signaling events during early heart development are critical for proper lineage specification and segregation and provide additional detail into these processes in mouse and human cardiogenesis.
2023-01-07 | GSE143226 | GEO
Project description:Transcriptional networks governing cardiac precursor cell (CPC) specification are incompletely understood due in part to limitations in distinguishing CPCs from non-cardiac mesoderm in early gastrulation. We leveraged detection of early cardiac lineage transgenes within a granular single cell transcriptomic time course of mouse embryos to identify emerging CPCs and describe their transcriptional profiles. Mesp1, a transiently-expressed mesodermal transcription factor (TF), is canonically described as an early regulator of cardiac specification. However, we observed perdurance of CPC transgene-expressing cells in Mesp1 mutants, albeit mis-localized, prompting us to investigate the scope of Mesp1’s role in CPC emergence and differentiation. Mesp1 mutant CPCs failed to robustly activate markers of cardiomyocyte maturity and critical cardiac TFs, yet they exhibited transcriptional profiles resembling cardiac mesoderm progressing towards cardiomyocyte fates. Single cell chromatin accessibility analysis defined a Mesp1-dependent developmental breakpoint in cardiac lineage progression at a shift from mesendoderm transcriptional networks to those necessary for cardiac patterning and morphogenesis. These results reveal Mesp1-independent aspects of early CPC specification and underscore a Mesp1-dependent regulatory landscape required for progression through cardiogenesis.
2023-04-07 | GSE208153 | GEO
Project description:Self-organisation and coordinated morphogenesis of multiple cardiac lineages is essential for the development and function of the heart. However, the absence of a human in vitro model that mimics the basic lineage architecture of the heart hinders research into developmental mechanisms and congenital defects. Here, we describe the establishment of a reliable, lineage-controlled and high-throughput cardiac organoid platform. We show that cardiac mesoderm derived from human pluripotent stem cells robustly self-organises and differentiates into cardiomyocytes forming a cavity. Co-differentiation of cardiomyocytes and endothelial cells from cardiac mesoderm within these structures is required to form a separate endothelial layer. As in vivo, the epicardium engulfs these cardiac organoids, migrates into the cardiomyocyte layer and differentiates. Thus, the cardiac organoid platform represents a powerful resource for the quantitative and mechanistic analysis of early human cardiogenesis that is otherwise inaccessible.
2021-05-20 | GSE148025 | GEO
Project description:Transcriptional networks governing cardiac precursor cell (CPC) specification are incompletely understood due in part to limitations in distinguishing CPCs from non-cardiac mesoderm in early gastrulation. We leveraged detection of early cardiac lineage transgenes within a granular single cell transcriptomic time course of mouse embryos to identify emerging CPCs and describe their transcriptional profiles. Mesp1, a transiently-expressed mesodermal transcription factor (TF), is canonically described as an early regulator of cardiac specification. However, we observed perdurance of CPC transgene-expressing cells in Mesp1 mutants, albeit mis-localized, prompting us to investigate the scope of Mesp1’s role in CPC emergence and differentiation. Mesp1 mutant CPCs failed to robustly activate markers of cardiomyocyte maturity and critical cardiac TFs, yet they exhibited transcriptional profiles resembling cardiac mesoderm progressing towards cardiomyocyte fates. Single cell chromatin accessibility analysis defined a Mesp1-dependent developmental breakpoint in cardiac lineage progression at a shift from mesendoderm transcriptional networks to those necessary for cardiac patterning and morphogenesis. These results reveal Mesp1-independent aspects of early CPC specification and underscore a Mesp1-dependent regulatory landscape required for progression through cardiogenesis. This SuperSeries is composed of subseries.
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