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A context-specific cardiac Beta-catenin and GATA4 interaction influences TCF7L2 occupancy and remodels chromatin driving disease progression in the adult heart [ChIP-seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE97761 | GEO | 2018/01/23

REPOSITORIES: GEO

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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.

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.

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A context-specific cardiac Beta-catenin and GATA4 interaction influences TCF7L2 occupancy and remodels chromatin driving disease progression in the adult heart [ChIP-seq]

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