The Isl1/Ldb1 complex orchestrates heart-specific chromatin organization and transcriptional regulation

Cardiac stem/progenitor cells hold great potential for regenerative therapies however the mechanisms regulating their expansion and differentiation remain insufficiently defined. Here we show that the multi-adaptor protein Ldb1 is a central regulator of cardiac progenitor cell differentiation and second heart field (SHF) development. Mechanistically, we demonstrate that Ldb1 binds to the key regulator of SHF progenitors Isl1 and protects it from proteasomal degradation. Furthermore, the Isl1/Ldb1 complex promotes long-range promoter-enhancer interactions at the loci of the core cardiac transcription factors Mef2c and Hand2. Chromosome conformation capture followed by sequencing identified surprisingly specific, Ldb1-mediated interactions of the Isl1/Ldb1 responsive Mef2c anterior heart field enhancer with genes which play key roles in cardiac progenitor cell function and cardiovascular development. Importantly, the expression of these genes was 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.