Distinct TCF7L2 genomic occupancies discern chromatin states in the neonatal and diseased mammalian myocardium [ChIP-Seq]

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. Genome-wide TCF7L2, GATA4 and H3K27ac binding profiles in postnatal day 6 (P6) murine cardiac ventricles