Distinct TCF7L2 genomic occupancies discern chromatin states in the neonatal and diseased mammalian myocardium [ChIP-Seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE121235 | GEO | 2021/08/02
REPOSITORIES: GEO
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Project description:In mammals, Wnt pathway is activated during both heart regeneration post-injury and disease. Our previous work described the role of nuclear Wnt effectors B-catenin and Transcription factor 7-like 2 (TCF7L2) in heart disease progression; revealing GATA4 as a Wnt-repressor in the healthy adult heart. However, there is an urgent need to dissect molecular players distinguishing regenerative vs. disease-specific responses. In this study, we report a GATA4-B-catenin interaction in the regenerative neonatal myocardium, despite high TCF7L2 expression. TCF7L2 displayed strikingly unique genomic occupancies: proximal in neonatal and distal in diseased hearts. Integrative genomic and transcriptomic analyses showed that TCF7L2 differentially occupied and regulated fatty acid metabolic genes in the neonatal; and cardiac developmental and vasculogenesis genes in the diseased hearts, clearly discerning these two cardiac states. De-novo motif search identified TEAD as a commonly enriched motif in both TCF7L2 and GATA4-bound regions in the neonatal hearts, suggesting its potential role in providing a regenerative context to this GATA4-B-catenin interaction. Altogether, our study mapped for the first time, novel genome-wide TCF7L2 and GATA4 targets in the neonatal hearts and identified stage-specific roles for the cardiac Wnt-GATA4 complex. These findings demonstrate strong context-specificity of the cardiac Wnt-nuclear complex, which can be further exploited for therapeutic avenues. Purpose: The aim of this study was to investigate the transcriptome profiles (RNA-seq) of WT postnatal day 6 murine cardiac ventricles; and compare them to our previously published (GSE97762) adult and diseased myocardium transcriptomes. Methods: P6 cardiac ventricular tissue mRNA profiles were obtained using deep sequencing, in triplicates, using Illumina HiSeq4000. The sequence reads that passed quality filters were analyzed at the transcript isoform level with TopHat followed by DESeq2. qPCR validation was performed using TaqMan and SYBR Green assays Conclusions: Our study identified distinct transcriptomic signatures of P6 murine cardiac ventricles, in comparison to healthy or diseased adult heart. Particularly, despite high Wnt signaling activities and cardiomyocytes cell cycling in both P6 and diseased hearts, P6 hearts are regenerative in nature, while the diseased hearts are not.
2021-08-02 | GSE121234 | GEO
Project description:Activation of the evolutionarily conserved, developmental Wnt pathway has been reported during maladaptive cardiac remodeling. Although the function of Wnt-transcriptional activation in development is well described, the consequences of Wnt pathway activation, as well as its cardiac-specific regulatory role in the adult heart, is largely unknown. We show that β-catenin and Transcription factor 7-like 2 (TCF7L2), the main nuclear components of the Wnt-transcriptional cascade, and their transcriptional activity are increased upon pathological remodeling in both murine and human hearts. To understand the consequences of increased Wnt signaling pathway activity, we utilized an in vivo mouse model in which β-catenin is acutely stabilized in adult cardiomyocytes (CM), leading to increased ventricular TCF7L2 expression and activation of its target genes. Mice with stabilized β-catenin displayed cardiac hypertrophy, increased mortality, reduced cardiac function and altered calcium homeostasis, similar to experimentally induced hypertrophy. Moreover, we observed a re-activation of Wnt-dependent developmental gene programs including activation of the Wnt/β-catenin-independent pathway, increased CM cell cycling with poly-nucleation and cytoskeletal disorganization, underscoring a central role in adult tissue remodeling. By integrating transcriptome analyses and genome-wide occupancy (ChIP-seq) of the endogenous ventricular TCF7L2, we show that upon aberrant Wnt activation, TCF7L2 induces context and Wnt-specific gene regulation in pathological remodeling. Interestingly, β-catenin stabilized ventricles showed increased histone H3 lysine 27 acetylation (H3K27ac) and TCF7L2 recruitment to novel disease-associated gene-specific enhancers. Importantly, using integrative motif analyses and experimental evidences, our data uncovered a role for GATA4 as a cardiogenic regulator of TCF7L2/β-catenin complex and established a paradigm for cell-specific effects of Wnt signaling. Altogether, our studies unraveled the nuclear Wnt-TCF7L2-associated chromatin landscape and its role in adult tissue remodeling leading to heart failure.
2018-01-23 | GSE97761 | GEO
Project description:Summary: Activation of the evolutionarily conserved, developmental Wnt pathway has been reported during maladaptive cardiac remodeling. Although the function of Wnt-transcriptional activation in development is well described, the consequences of Wnt pathway activation, as well as its cardiac-specific regulatory role in the adult heart, is largely unknown. We show that β-catenin and Transcription factor 7-like 2 (TCF7L2), the main nuclear components of the Wnt-transcriptional cascade, and their transcriptional activity are increased upon pathological remodeling in both murine and human hearts. To understand the consequences of increased Wnt signaling pathway activity, we utilized an in vivo mouse model in which β-catenin is acutely stabilized in adult cardiomyocytes (CM), leading to increased ventricular TCF7L2 expression and activation of its target genes. Mice with stabilized β-catenin displayed cardiac hypertrophy, increased mortality, reduced cardiac function and altered calcium homeostasis, similar to experimentally induced hypertrophy. Moreover, we observed a re-activation of Wnt-dependent developmental gene programs including activation of the Wnt/β-catenin-independent pathway, increased CM cell cycling with poly-nucleation and cytoskeletal disorganization, underscoring a central role in adult tissue remodeling. By integrating transcriptome analyses and genome-wide occupancy (ChIP-seq) of the endogenous ventricular TCF7L2, we show that upon aberrant Wnt activation, TCF7L2 induces context and Wnt-specific gene regulation in pathological remodeling. Interestingly, β-catenin stabilized ventricles showed increased histone H3 lysine 27 acetylation (H3K27ac) and TCF7L2 recruitment to novel disease-associated gene-specific enhancers. Importantly, using integrative motif analyses and experimental evidences, our data uncovered a role for GATA4 as a cardiogenic regulator of TCF7L2/β-catenin complex and established a paradigm for cell-specific effects of Wnt signaling. Altogether, our studies unraveled the nuclear Wnt-TCF7L2-associated chromatin landscape and its role in adult tissue remodeling leading to heart failure. Purpose: The aim of this study was to compare transcriptome profiles (RNA-seq) of normal (containing a Cre recombinase positive locus- Cre "positive" control with a WT β-catenin locus; to eliminate effects of Cre-mediated cardiac toxicity) and β-catenin stabilized murine adult cardiac ventricles. Methods: Adult cardiac tissue mRNA profiles for normal and Wnt-activated mice were obtained using deep sequencing, in triplicates, using Illumina HiSeq2000. The sequence reads that passed quality filters were analyzed at the transcript isoform level with TopHat followed by DESeq2. qPCR validation was performed using TaqMan and SYBR Green assays Conclusions: Our study represents the first detailed analysis of the processes triggered upon Wnt activation in the adult heart, which was so far, not investigated. We report that this Wnt activation in the adult heart maintains its developmental function; however due to the lack of adequate developmental plasticity in the adult heart, culminates in pathological remodeling.
2018-01-23 | GSE97762 | GEO
Project description:The inability of the adult mammalian heart to regenerate represents a fundamental barrier in heart failure management. In contrast, the neonatal heart retains a transient regenerative capacity, but the underlying mechanisms are not fully understood. Wnt/β-catenin signaling has been suggested as a key cardio-regenerative pathway. Here, we show that Wnt/β-catenin signaling potentiates neonatal mouse cardiomyocyte proliferation in vivo and immature human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) proliferation in vitro. In contrast, Wnt/β-catenin signaling in adult mice is cardioprotective but fails to induce cardiomyocyte proliferation. Transcriptional profiling of neonatal mouse and hPSC-CM revealed a core Wnt/β-catenin-dependent transcriptional network governing cardiomyocyte proliferation. In contrast, β-catenin failed to re-engage this proliferative gene network in the adult heart, which instead reverted to a neonatal-like glycolytic program. These findings suggest that Wnt/β-catenin drives distinct transcriptional networks in regenerative and non-regenerative cardiomyocytes, which may contribute towards the inability of the adult heart to regenerate following injury.
2020-11-04 | GSE150521 | GEO
Project description:Background: The adult mammalian heart has limited capacity for regeneration following injury, whereas the neonatal heart can readily regenerate within a short period after birth. To uncover the molecular mechanisms underlying neonatal heart regeneration, we compared the transcriptomes and epigenomes of regenerative and non-regenerative mouse hearts over a 7-day time period following myocardial infarction. Methods: RNA-Seq, H3K27ac ChIP-Seq and H3K27me3 ChIP-Seq were performed on ventricular samples from regenerative P1 or non-regenerative P8 mouse hearts at +1.5d, +3d and +7d after MI or Sham surgery to assemble the transcriptome, active chromatin and repressed chromatin landscapes during neonatal heart regeneration. Dynamic enhancer landscapes from mouse hearts during cardiac development were analyzed using data from ENCODE. Effects on cardiomyocyte proliferation and cardiac function from selected factors identified in this study were tested using BrdU/EdU pulse-labeling or mouse models coupled with immunohistochemistry and echocardiography. Results: By integrating gene expression profiles with histone marks associated with active or repressed chromatin, we identified transcriptional programs underlying neonatal heart regeneration and the blockade to regeneration in later life. Our results reveal a unique immune response in regenerative hearts and an embryonic cardiogenic gene program that remains active during neonatal heart regeneration. Among the unique immune factors and embryonic genes associated with cardiac regeneration, we identified Ccl24, which encodes a cytokine, and Igf2bp3, which encodes an RNA-binding protein, as previously unrecognized regulators of cardiomyocyte proliferation. Conclusions: Our data provide insights into the molecular basis of neonatal heart regeneration and identify genes that might be modulated to promote heart regeneration.
2019-07-15 | GSE123867 | GEO
Project description:Background: The adult mammalian heart has limited capacity for regeneration following injury, whereas the neonatal heart can readily regenerate within a short period after birth. To uncover the molecular mechanisms underlying neonatal heart regeneration, we compared the transcriptomes and epigenomes of regenerative and non-regenerative mouse hearts over a 7-day time period following myocardial infarction. Methods: RNA-Seq, H3K27ac ChIP-Seq and H3K27me3 ChIP-Seq were performed on ventricular samples from regenerative P1 or non-regenerative P8 mouse hearts at +1.5d, +3d and +7d after MI or Sham surgery to assemble the transcriptome, active chromatin and repressed chromatin landscapes during neonatal heart regeneration. Dynamic enhancer landscapes from mouse hearts during cardiac development were analyzed using data from ENCODE. Effects on cardiomyocyte proliferation and cardiac function from selected factors identified in this study were tested using BrdU/EdU pulse-labeling or mouse models coupled with immunohistochemistry and echocardiography. Results: By integrating gene expression profiles with histone marks associated with active or repressed chromatin, we identified transcriptional programs underlying neonatal heart regeneration and the blockade to regeneration in later life. Our results reveal a unique immune response in regenerative hearts and an embryonic cardiogenic gene program that remains active during neonatal heart regeneration. Among the unique immune factors and embryonic genes associated with cardiac regeneration, we identified Ccl24, which encodes a cytokine, and Igf2bp3, which encodes an RNA-binding protein, as previously unrecognized regulators of cardiomyocyte proliferation. Conclusions: Our data provide insights into the molecular basis of neonatal heart regeneration and identify genes that might be modulated to promote heart regeneration.
2019-07-15 | GSE123863 | GEO
Project description:For a short period of time in mammalian neonates, the mammalian heart can regenerate via cardiomyocyte proliferation. This regenerative capacity is largely absent in adults. In other organisms, including zebrafish, damaged hearts can regenerate throughout their lifespans. Many studies have been performed to understand the mechanisms of cardiomyocyte de-differentiation and proliferation during heart regeneration however, the underlying reason why adult zebrafish and young mammalian cardiomyocytes are primed to enter cell cycle have not been identified. Here we show the primed state of a pro-regenerative cardiomyocyte is dictated by its amino acid profile and metabolic state. Adult zebrafish cardiomyocyte regeneration is a result of amino acid-primed mTOR activation. Zebrafish and neonatal mouse cardiomyocytes display elevated glutamine levels, predisposing them to amino acid-driven activation of mTORC1. Injury initiates Wnt/β-catenin signalling that instigates primed mTORC1 activation, Lin28 expression and metabolic remodeling necessary for zebrafish cardiomyocyte regeneration. These studies reveal a unique mTORC1 primed state in zebrafish and mammalian regeneration competent cardiomyocytes.
2022-02-15 | PXD011791 | Pride
Project description:Myocardial infarction (MI) leads to cardiomyocyte death, which triggers an immune response that clears debris and restores tissue integrity. In the adult heart, the immune system facilitates scar formation, which repairs the damaged myocardium but compromises cardiac function. In neonatal mice, the heart can regenerate fully without scarring following MI; however, this regenerative capacity is lost by P7. The signals that govern neonatal heart regeneration are unknown. By comparing the immune response to MI in mice at P1 and P14, we identified differences in the magnitude and kinetics of monocyte and macrophage responses to injury. Using a cell-depletion model, we determined that heart regeneration and neoangiogenesis following MI depends on neonatal macrophages. Neonates depleted of macrophages were unable to regenerate myocardia and formed fibrotic scars, resulting in reduced cardiac function and angiogenesis. Immunophenotyping and gene expression profiling of cardiac macrophages from regenerating and nonregenerating hearts indicated that regenerative macrophages have a unique polarization phenotype and secrete numerous soluble factors that may facilitate the formation of new myocardium. Our findings suggest that macrophages provide necessary signals to drive angiogenesis and regeneration of the neonatal mouse heart. Modulating inflammation may provide a key therapeutic strategy to support heart regeneration. Total RNA was isolated from CD11b+Ly6G- cells sorted from hearts 3 days following ligation of LAD. 6 samples total: Triplicates of cells from P1 mice and from P14 mice
2014-01-31 | E-GEOD-54530 | biostudies-arrayexpress
Project description:Heterozygous mutations in GATA4 cause congenital heart defects and cardiomyopathy through unknown mechanisms. To gain insights into the open chromatin status during human cardiac development due to GATA4 heterozygosity, we performed ATAC-seq of wildtype and GATA4-G296S diseased cardiac progenitors.
2016-12-15 | GSE85630 | GEO
Project description:Heterozygous mutations in GATA4 cause congenital heart defects and cardiomyopathy through unknown mechanisms. To gain insights into the trancriptome perturbations during human cardiac development due to GATA4 heterozygosity, we performed RNA-seq of isogenic wildtype and GATA4-G296S diseased cardiac progenitors (CPCs) and cardiomyocytes (CMs).
2016-12-15 | GSE85623 | GEO