LncRNA HBL1 Recruits Polycomb Repressive Complex 2 on Essential Cardiogenic Genes to Orchestrate Human Cardiogenesis
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PROVIDER: PRJNA628623 | ENA |
REPOSITORIES: ENA
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Project description:Rationale: Cardiac development is a complex process that results in the first integrated, multi-lineage embryonic tissue. Imperfect developmental progression leads to congenital heart disease, the most common birth defect with developmental corruption affecting more than 1% of all live births. Interrogation of individual genes has provided the backbone for cardiac developmental biology, yet a comprehensive transcriptome derived from natural cardiogenesis is required to establish an unbiased roadmap to gauge innate developmental milestones necessary for stem cell-based differentiation and in vitro disease modeling. Objective: Establish a contextual expression database of spatial-temporal cardiac structures, and validate a predictive tool to diagnose and predict cardiogenic outcomes from individual pluripotent stem cell lines. Methods and Results: Stage-specific cardiac structures were dissected from eight distinctive embryonic time points to produce a genome-wide expressome analysis across the spectrum of early to late cardiogenesis. Hierarchical clustering of the time course dataset demonstrated discrete gene expression profiles during natural embryonic development. In reference to the native cardiogenic expression roadmap, disruptive iPSC-derived cardiac expression profiles were revealed from pro-cardiogenic 3-factor (SOX2, OCT4, KLF4) compared to non-cardiogenic 4-factor (addition of c-MYC) reprogramming regimens upon stage-specific differentiation. Expression of cardiac-related genes from 3F-iPSC differentiated in vitro at day 0, 5, and 11 recapitulated expression of natural embryos at days 0, E7.5-E8.5, and E14.5-E18.5, respectively. In contrast, 4F-iPSC demonstrated variable gastrulation gene expression profiles beginning at day 5 of differentiation. Differential gene expression within the pluripotent ground state between the archetypical high cardiogenic potential of embryonic stem cells recapitulated in 3F-iPSC vs. the low cardiogenic potential of 4F-iPSC revealed 23 distinguishing candidate genes. Upon subsequent differentiation, cell line-specific gene expression differences were magnified to 399 genes at day 5 and 726 genes at day 11. A confirmed panel of 20 genes, differentially expressed between high and low cardiogenic cell lines, was transformed into a predictive score that was sufficient to correctly rank independent iPSC lines according to cardiogenic potential. Conclusions: Transcriptome analysis attuned to the embryonic developing heart provides a robust platform to probe coordinated cardiac specification and maturation from stem cell-based cardiogenesis model systems. Based on this genome-wide expressome roadmap, a panel of pre-cardiac genes was extracted that allowed differential prognosis of cardiogenic competency from individual reprogrammed cell lines at the pluripotent state. The overall experimental design includes 3 time points (Day0, Day5, Day11) and 3 different stem cell lines: R1 embryonic stem cells (ESCs), H9 induced pluripotent stem cells (H9-iPSCs) generated/reprogrammed by 3 transcription factors (called 3F-iPSCs), and 19BL induced pluripotent stem cells (19BL-iPSCs) generated/reprogrammed by 4 transcription factors (called 4F-iPSC). At each time point, each cell line has 3 biological replicates. In total, there are 27 samples. R1-embryonic stem cells (R1-ESCs): Day0 undifferentiated ESCs - 3 biological replicates, Differentiated for 5 days (Day5) - 3 biological replicates, Differentiated for 11 days (Day11) - 3 biological replicates. 3F-iPSC (H9 iPSCs): Day 0 undifferentiated - 3 biological replicates, Differentiated for 5 days (Day5) - 3 biological replicates, Differentiated for 11 days (Day11) - 3 biological replicates. 4F-iPSC (19BL-iPSCs): Day0 undifferentiated - 3 biological replicates, Differentiated for 5 days (Day5) - 3 biological replicates, Differentiated for 11 days (Day11) - 3 biological replicates.
2013-09-23 | E-GEOD-43197 | biostudies-arrayexpress
Project description:Rationale: Cardiac development is a complex process that results in the first integrated, multi-lineage embryonic tissue. Imperfect developmental progression leads to congenital heart disease, the most common birth defect with developmental corruption affecting more than 1% of all live births. Interrogation of individual genes has provided the backbone for cardiac developmental biology, yet a comprehensive transcriptome derived from natural cardiogenesis is required to establish an unbiased roadmap to gauge innate developmental milestones necessary for stem cell-based differentiation and in vitro disease modeling. Objective: Apply the contextual expression database of spatial-temporal cardiac structures (published in another manuscript by Li X. from the same group) to diagnose and predict cardiogenic outcomes from individual pluripotent stem cell lines. Methods and Results: Stage-specific cardiac structures were dissected from eight distinctive embryonic time points to produce a genome-wide expressome analysis across the spectrum of early to late cardiogenesis. Hierarchical clustering of the time course dataset demonstrated discrete gene expression profiles during natural embryonic development. In reference to the native cardiogenic expression roadmap, disruptive iPSC-derived cardiac expression profiles were revealed from pro-cardiogenic 3-factor (SOX2, OCT4, KLF4) compared to non-cardiogenic 4-factor (addition of c-MYC) reprogramming regimens upon stage-specific differentiation. Expression of cardiac-related genes from 3F-iPSC differentiated in vitro at day 0, 5, and 11 recapitulated expression of natural embryos at days 0, E7.5-E8.5, and E14.5-E18.5, respectively. In contrast, 4F-iPSC demonstrated variable gastrulation gene expression profiles beginning at day 5 of differentiation. Differential gene expression within the pluripotent ground state between the archetypical high cardiogenic potential of embryonic stem cells recapitulated in 3F-iPSC vs. the low cardiogenic potential of 4F-iPSC revealed 23 distinguishing candidate genes. Upon subsequent differentiation, cell line-specific gene expression differences were magnified to 399 genes at day 5 and 726 genes at day 11. A confirmed panel of 20 genes, differentially expressed between high and low cardiogenic cell lines, was transformed into a predictive score that was sufficient to correctly rank independent iPSC lines according to cardiogenic potential. Conclusions: Transcriptome analysis attuned to the embryonic developing heart provides a robust platform to probe coordinated cardiac specification and maturation from stem cell-based cardiogenesis model systems. Based on this genome-wide expressome roadmap, a panel of pre-cardiac genes was extracted that allowed differential prognosis of cardiogenic competency from individual reprogrammed cell lines at the pluripotent state.
2013-09-23 | GSE43197 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-06-10 | GSE149409 | GEO
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.
2014-05-19 | E-GEOD-51483 | biostudies-arrayexpress
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.
2014-05-19 | GSE51483 | GEO
Project description:We reported loss of HBL1 lnRNA promoted cardiogenesis and the interaction of HBL1-JARID2 in hPSCs. Here we used specific JARID2 antibody to pull down their binding genomic DNAs in hPSCs, respectively, which let us know the potential genes regulated by HBL1-JARID2 during cardiogenesis. 1% Input samples were collected from the same samples after chromatin shearing.
2021-06-10 | GSE149288 | GEO
Project description:We reported loss of HBL1 lnRNA promoted cardiogenesis and the interaction of HBL1-EED in hiPSCs. Here we used specific EED and H3K27me3 antibodies to pull down their binding genomic DNAs in hiPSCs, respectively, which let us know the potential genes regulated by HBL1-EED-H3K27me3 during cardiogenesis. 1% Input samples were collected from the same samples after chromatin shearing.
2021-06-10 | GSE149323 | GEO
Project description:We reported loss of HBL1 lncRNA promoted cardiogenesis. Here we wanted to know the genomewide gene expression profiles caused by HBL1 KO during cardiac differentiation.
2021-06-10 | GSE149408 | GEO
Project description:Here we extend our previous EMLO gastruloid technology to cardiac (EMLOC) with the generation of interconnected neuro-gut-cardiac interconnected multilineages. The contractile EMLOCs recapitulate numerous developmental features of heart tube formation and specialization, cardiomyocyte differentiation and remodeling phases, epicardium, ventricular wall morphogenesis, and formation of the putative outflow tract. Cardiogenesis in EMLOCs originates anterior to the gut tube primordium and we observe neurons that progressively populate the cardiogenic region in a pattern that mirrors the spatial distribution of neurons in heart innervation. The EMLOC mode represents the first multi-lineage advancement of neuro-cardiac lineages in a gastruloid model that parallels human cardiogenesis with neurogenesis.
2022-05-06 | GSE194356 | GEO
Project description:Fibroblasts can be directly reprogrammed toward a cardiac fate by introducing cardiogenic transcription factors (TFs), although the underlying mechanisms of the cardiac reprogramming process remain unclear. Three cardiac TFs, GATA4, MEF2C, and Tbx5 (referred to as GMT) can activate cardiac genes in fibroblasts and their cardiogenic activity is enhanced by the Hand2 TF and the Akt1 kinase. To understand the mechanistic basis of cardiac reprogramming, we performed a genome-wide analysis of cardiogenic TF binding sites and active enhancers, which were annotated by H3K27ac histone modification, during the reprogramming process. We found that cardiogenic TFs rapidly co-occupy core regulatory elements of cardiac genes and activate myriad cardiac enhancers that are enriched predominantly in Mef2 binding sites. Addition of Hand2 and Akt1 to the GMT reprogramming cocktail expands the spectrum of co-occupied active cardiac enhancers. As reprogramming proceeds over time, reprogramming TFs continue to activate additional cardiac enhancers, which are also enriched for Mef2 motifs, while fibroblast enhancers are silenced. This transition of the enhancer landscape strongly correlated with changes in the fibroblast and cardiac transcriptome. To test the relevance of cardiac reprogramming enhancers to the regulation of cardiogenesis in vivo, we assayed a collection of reprogramming enhancers in transgenic mouse embryos and found that they directed highly specific expression patterns in the developing heart. Our findings demonstrate that Hand2 and Akt1 enhance reprogramming by facilitating cardiac enhancer occupancy and identify Mef2 as a central effector of cardiac reprogramming, which coordinates the actions of accessory factors across a broad landscape of cardiac enhancers.
2019-04-15 | GSE112316 | GEO