A context-specific cardiac β-catenin and GATA4 interaction influences TCF7L2 occupancy and remodels chromatin driving disease progression in the adult heart

Chromatin remodelling precedes transcriptional and structural changes in heart failure. A body of work suggests roles for the developmental Wnt signalling pathway in cardiac remodelling. Hitherto, there is no evidence supporting a direct role of Wnt nu-clear components in regulating chromatin land-scapes in this process. We show that transcrip-tionally active, nuclear, phosphorylated(p)Ser675-␤-catenin and TCF7L2 are upregulated in diseased murine and human cardiac ventricles. We report that inducible cardiomyocytes (CM)-specific pSer675-␤-catenin accumulation mimics the disease situation by triggering TCF7L2 expression. This enhances ac-tive chromatin, characterized by increased H3K27ac and TCF7L2 occupancies to cardiac developmental and remodelling genes in vivo. Accordingly, tran-scriptomic analysis of ␤-catenin stabilized hearts shows a strong recapitulation of cardiac develop-mental processes like cell cycling and cytoskeletal remodelling. Mechanistically, TCF7L2 co-occupies distal genomic regions with cardiac transcription factors NKX2–5 and GATA4 in stabilized-␤-catenin hearts. Validation assays revealed a previously un-recognized function of GATA4 as a cardiac repres-sor of the TCF7L2/␤-catenin complex in vivo, thereby defining a transcriptional switch controlling disease progression. Conversely, preventing ␤-catenin acti-vation post-pressure-overload results in a downreg-ulation of these novel TCF7L2-targets and rescues cardiac function. Thus, we present a novel role for TCF7L2/␤-catenin in CMs-specific chromatin modu-lation, which could be exploited for manipulating the ubiquitous Wnt pathway.