The Isl1/Ldb1 Complex Orchestrates Genome-wide Chromatin Organization to Instruct Differentiation of Multipotent Cardiac Progenitors

Abstract

SUMMARY 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.

The stage-dependent roles of Ldb1 and functional redundancy with Ldb2 in mammalian retinogenesis

“…S4). Ldb1 may therefore be required to maintain stability of Isl1 protein in retina, similar to observations made in cardiac progenitors (Caputo et al, 2015).…”

“…S5). Ldb1 was already shown to function in stabilizing the Isl1 protein in cardiac progenitors, these results suggest a similar role in the retina (Caputo et al, 2015). In contrast to the loss of Isl1 protein seen in Ldb1/Ldb2-deficient retinas, Lhx2 was maintained in the mutant cells throughout most of embryogenesis and was reduced only close to birth (E18.5, Fig.…”

“…Ldb1 has been shown to fulfill several important functions: it has an essential role in the development of the CNS and is crucial for specification and maintenance of hematopoietic stem cells (Li et al, 2011). Moreover, Ldb1, together with Isl1, is a key early regulator of mammalian limb and cardiac development (Narkis et al, 2012;Caputo et al, 2015).…”

LMO2 Oncoprotein Stability in T-Cell Leukemia Requires Direct LDB1 Binding

“…These proteins may compete with LMO2 for LDB1 binding (59). Importantly, it was recently shown that LDB1 protects the related LIM homeodomain factor ISL1 from degradation during cardiac development (66). ISL and LHX proteins, such as ISL2 and LHX9 identified in this work, have their own DNA-binding homeodomains that may confer additional target gene diversity to LDB1/SSBP, which may be important for leukemic cell growth.…”

Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice

“…work rules the activity of Isl1 (46,47), to which we added a decisive component. We demonstrated that Isl1 is repressed by hypoxia responses through HES1/HIF1α-dependent recruitment of SIRT1 to the Isl1 gene and by activation of Sirt1.…”