title: The Isl1/Ldb1 Complex Orchestrates Genome-wide Chromatin Organization to Instruct Differentiation of Multipotent Cardiac Progenitors.
abstract: 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.
authors: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors: Luca
authors: L
authors: Caputo
authors: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors: Hagen R
authors: HR
authors: Witzel
authors: Department of Cell Biology, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands.
authors: Petros
authors: P
authors: Kolovos
authors: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors: Sirisha
authors: S
authors: Cheedipudi
authors: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors: Mario
authors: M
authors: Looso
authors: Department of Cell Biology, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands; School of Human and Life Sciences, Canterbury Christ Church University, Canterbury, Kent CT1 1QU, UK.
authors: Athina
authors: A
authors: Mylona
authors: Center for Biomics, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands.
authors: Wilfred F J
authors: WF
authors: van IJcken
authors: I. Medical Department, Cardiology, Klinikum rechts der Isar, Technical University, 81675 Munich, Germany.
authors: Karl-Ludwig
authors: KL
authors: Laugwitz
authors: Department of Medicine, Skaggs School of Pharmacy, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Sylvia M
authors: SM
authors: Evans
authors: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors: Thomas
authors: T
authors: Braun
authors: Department of Cell Biology, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands; Laboratory of Molecular Hematopoiesis, CEA/DSV/iRCM/LHM, INSERM UMR967, 92265 Fontenay-aux-Roses, France; Laboratory of Excellence GR-Ex, 75015, Paris, France.
authors: Eric
authors: E
authors: Soler
authors: Department of Cell Biology, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands.
authors: Frank
authors: F
authors: Grosveld
authors: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany; Medical Faculty, University of Frankfurt, 60590 Frankfurt am Main, Germany. Electronic address: gergana.dobreva@mpi-bn.mpg.de.
authors: Gergana
authors: G
authors: Dobreva
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D004843:Epistasis, Genetic; D018507:Gene Expression Regulation, Developmental; D056426:Genetic Loci; D016678:Genome; D057809:HEK293 Cells; D006321:Heart / Q000196:embryology; D006801:Humans; D060588:LIM Domain Proteins / Q000737:chemistry / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins / Q000378:metabolism*; D064326:MEF2 Transcription Factors / Q000378:metabolism; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D009690:Nucleic Acid Conformation; D038081:Organogenesis; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D014157:Transcription Factors / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; D064326:MEF2 Transcription Factors; D046988:Proteasome Endopeptidase Complex; D014157:Transcription Factors; C498766:Hand2 protein, mouse; C102084:Ldb1 protein, mouse; C578041:Mef2c protein, mouse; C063843:insulin gene enhancer binding protein Isl-1
keywords: AHF enhancer; Hand2; Isl1; Ldb1; Mef2c; cardiac progenitors; cardiomyocyte differentiation; enhancer-promoter interactions; genome organization; second heart field