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Series GSE97761 Query DataSets for GSE97761
Status Public on Jan 23, 2018
Title A context-specific cardiac Beta-catenin and GATA4 interaction influences TCF7L2 occupancy and remodels chromatin driving disease progression in the adult heart [ChIP-seq]
Organism Mus musculus
Experiment type Genome binding/occupancy profiling by high throughput sequencing
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.
Overall design Genome-wide TCF7L2 and H3K27ac binding profiles in wild type and β-catenin stabilized murine adult cardiac ventricles
Contributor(s) Iyer LM, Zelarayan LC
Citation(s) 29394407, 36681760
Submission date Apr 13, 2017
Last update date Feb 08, 2023
Contact name Laura C Zelarayan
Organization name University Medical Center, Goettingen
Department Institute of Pharmacology and Toxicology
Street address Robert-Koch Strasse 40
City Goettingen
State/province Lower Saxony
ZIP/Postal code 37075
Country Germany
Platforms (1)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
Samples (13)
GSM2577065 TCF7L2_Wntup_1
GSM2577066 TCF7L2_Wntup_2
GSM2577067 H3K27ac_Wntup_1
This SubSeries is part of SuperSeries:
GSE97763 A context-specific cardiac Beta-catenin and GATA4 interaction influences TCF7L2 occupancy and remodels chromatin driving disease progression in the adult heart
BioProject PRJNA382837
SRA SRP103873

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SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE97761_H3K27ac_Wntup_bamcov.bigwig 119.1 Mb (ftp)(http) BIGWIG
GSE97761_H3K27ac_normal_bamcov.bigwig 49.4 Mb (ftp)(http) BIGWIG
GSE97761_TCF7L2_Wntup_bamcov.bigwig 130.4 Mb (ftp)(http) BIGWIG
GSE97761_TCF7L2_normal_bamcov.bigwig 132.3 Mb (ftp)(http) BIGWIG
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