Résumé
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 Ldb1 is a central regulator of genome organization in cardiac progenitor cells, which is crucial for cardiac lineage differentiation and heart development. We demonstrate that Ldb1 binds to the key regulator of cardiac progenitors, Isl1, and protects it from degradation. Furthermore, the Isl1/Ldb1 complex promotes long-range enhancer-promoter interactions at the loci of the core cardiac transcription factors Mef2c and Hand2. Chromosome conformation capture followed by sequencing identified specific Ldb1-mediated interactions of the Isl1/Ldb1 responsive Mef2c anterior heart field enhancer with genes that 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.
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•Ldb1 is required for differentiation of multipotent cardiac progenitor cells•Ldb1 regulates second heart field development•Ldb1 protects the key regulator of cardiac progenitors, Isl1, from degradation•The Isl1/Ldb1 complex orchestrates cardiac-specific chromatin organization
Caputo et al. identify Ldb1 as a crucial regulator of cardiogenesis. Ldb1 binds the key cardiac transcription factor Isl1 and protects it from degradation. The stabilized Isl1/Ldb1 complex orchestrates a network for transcriptional regulation and coordination in three-dimensional space, driving cardiac progenitor cell differentiation and heart development.