Unknown,Transcriptomics,Genomics,Proteomics

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Expression data from Ad-β-catenin-GFP or Ad-GFP infected cardiomyocytes

ABSTRACT: The Wnt pathway is a key regulator of embryonic development, cell growth, differentiation, polarity formation, neural development, carcinogenesis, and stem cell self-renewal, and deregulation of the Wnt signalling is associated with many human disease. The central player in the Wnt pathway is β-catenin, A recent study has shown that β-catenin/Tcf/Lef signaling pathway is an essential growth-regulatory pathway in cardiomyocytes. We used DNA microarrays to detail the global trends in gene expression underlying β-catenin-overexpressed cardiomyocytes and identified distinct classes of up- or down-regulated genes during this process. Our findings suggest that β-catenin plays a critical role in regulating cardiac dysfunction at transcriptional level and may provide novel insight into how β-catenin modulates heart diseases. Cardiomyocytes were infected with GFP control or β-catenin adenoviruses for RNA extraction and hybridization on Affymetrix microarrays. We sought to define the effects of β-catenin on the global programme of gene expression in primary cardiomyocytes. To that end, neonatal rat cardiomyocytes were infected with GFP control (G) or β-catenin adenovirus (B) for 24 hours.

ORGANISM(S): Rattus norvegicus

SUBMITTER: junjie li

PROVIDER: E-GEOD-34772 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

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Expression data from Ad-β-catenin-GFP or Ad-GFP infected cardiomyocytes

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