Mus musculus. Mus musculus

Cardiac progenitor cells hold great potential for regenerative therapies in heart disorders, however, the mechanisms regulating their expansion and differentiation remain poorly defined. Here we show that the multi-adaptor protein Ldb1, is a central regulator of cardiac differentiation and second heart field development (SHF). Mechanistically, we demonstrate that Ldb1 binds to the key regulator of SHF development Isl1 and protects it from proteasomal degradation. Furthermore, the Isl1/Ldb1 complex promotes long-range promoter enhancer interactions within the loci of Mef2c and Hand2, key regulators of cardiogenesis. Chromosome conformation capture (3C) technology followed by sequencing identified surprisingly specific, Ldb1-mediated interactions of the Isl1/Ldb1 responsive Mef2c anterior heart field (AHF) enhancer with genes which play key roles in cardiovascular development. Importantly, the expression of these genes was strongly downregulated upon Ldb1 depletion and Isl1/Ldb1 haplodeficiency. In conclusion, the Isl1/Ldb1 complex orchestrates a network for heart-specific transcriptional regulation and coordination in three-dimensional space during cardiogenesis.