PUBLICATION
The Isl1/Ldb1 Complex Orchestrates Genome-wide Chromatin Organization to Instruct Differentiation of Multipotent Cardiac Progenitors
- Authors
- Caputo, L., Witzel, H.R., Kolovos, P., Cheedipudi, S., Looso, M., Mylona, A., van IJcken, W.F., Laugwitz, K.L., Evans, S.M., Braun, T., Soler, E., Grosveld, F., Dobreva, G.
- ID
- ZDB-PUB-170214-128
- Date
- 2015
- Source
- Cell Stem Cell 17: 287-99 (Journal)
- Registered Authors
- Keywords
- AHF enhancer, Hand2, Isl1, Ldb1, Mef2c, cardiac progenitors, cardiomyocyte differentiation, enhancer-promoter interactions, genome organization, second heart field
- MeSH Terms
-
- Animals
- Organogenesis
- Myocytes, Cardiac/cytology*
- Myocytes, Cardiac/metabolism
- Protein Multimerization
- Nucleic Acid Conformation
- MEF2 Transcription Factors/metabolism
- Proteolysis
- Transcription Factors/metabolism*
- LIM Domain Proteins/chemistry
- LIM Domain Proteins/metabolism*
- Humans
- Genetic Loci
- Heart/embryology
- Gene Expression Regulation, Developmental
- DNA-Binding Proteins/chemistry
- DNA-Binding Proteins/metabolism*
- Epistasis, Genetic
- Multipotent Stem Cells/cytology*
- Multipotent Stem Cells/metabolism
- Protein Structure, Tertiary
- Chromatin/chemistry
- Chromatin/metabolism*
- Enhancer Elements, Genetic/genetics
- Proteasome Endopeptidase Complex/metabolism
- Cell Differentiation*
- HEK293 Cells
- Zebrafish
- Genome*
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- Cell Lineage
- LIM-Homeodomain Proteins/metabolism*
- Promoter Regions, Genetic/genetics
- Protein Binding
- PubMed
- 26321200 Full text @ Cell Stem Cell
Citation
Caputo, L., Witzel, H.R., Kolovos, P., Cheedipudi, S., Looso, M., Mylona, A., van IJcken, W.F., Laugwitz, K.L., Evans, S.M., Braun, T., Soler, E., Grosveld, F., Dobreva, G. (2015) The Isl1/Ldb1 Complex Orchestrates Genome-wide Chromatin Organization to Instruct Differentiation of Multipotent Cardiac Progenitors. Cell Stem Cell. 17:287-99.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping