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

Cell Stem Cell. 2015 Sep 3;17(3):287-99. doi: 10.1016/j.stem.2015.08.007. Epub 2015 Aug 27.


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.

Keywords: AHF enhancer; Hand2; Isl1; Ldb1; Mef2c; cardiac progenitors; cardiomyocyte differentiation; enhancer-promoter interactions; genome organization; second heart field.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Differentiation*
  • Cell Lineage
  • Chromatin / chemistry
  • Chromatin / metabolism*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism*
  • Enhancer Elements, Genetic / genetics
  • Epistasis, Genetic
  • Gene Expression Regulation, Developmental
  • Genetic Loci
  • Genome*
  • HEK293 Cells
  • Heart / embryology
  • Humans
  • LIM Domain Proteins / chemistry
  • LIM Domain Proteins / metabolism*
  • LIM-Homeodomain Proteins / metabolism*
  • MEF2 Transcription Factors / metabolism
  • Multipotent Stem Cells / cytology*
  • Multipotent Stem Cells / metabolism
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / metabolism
  • Nucleic Acid Conformation
  • Organogenesis
  • Promoter Regions, Genetic / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Proteolysis
  • Transcription Factors / metabolism*
  • Zebrafish


  • Basic Helix-Loop-Helix Transcription Factors
  • Chromatin
  • DNA-Binding Proteins
  • Hand2 protein, mouse
  • LIM Domain Proteins
  • LIM-Homeodomain Proteins
  • Ldb1 protein, mouse
  • MEF2 Transcription Factors
  • Mef2c protein, mouse
  • Transcription Factors
  • insulin gene enhancer binding protein Isl-1
  • Proteasome Endopeptidase Complex

Associated data

  • SRA/SRP055800