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ISL1 and JMJD3 synergistically control cardiac differentiation of embryonic stem cells
- Source :
- Nucleic Acids Research
- Publication Year :
- 2016
-
Abstract
- ISL1 is expressed in cardiac progenitor cells and plays critical roles in cardiac lineage differentiation and heart development. Cardiac progenitor cells hold great potential for clinical and translational applications. However, the mechanisms underlying ISL1 function in cardiac progenitor cells have not been fully elucidated. Here we uncover a hierarchical role of ISL1 in cardiac progenitor cells, showing that ISL1 directly regulates hundreds of potential downstream target genes that are implicated in cardiac differentiation, through an epigenetic mechanism. Specifically, ISL1 promotes the demethylation of tri-methylation of histone H3K27 (H3K27me3) at the enhancers of key downstream target genes, including Myocd and Mef2c, which are core cardiac transcription factors. ISL1 physically interacts with JMJD3, a H3K27me3 demethylase, and conditional depletion of JMJD3 leads to impaired cardiac progenitor cell differentiation, phenocopying that of ISL1 depletion. Interestingly, ISL1 is not only responsible for the recruitment of JMJD3 to specific target loci during cardiac progenitor differentiation, but also modulates its demethylase activity. In conclusion, ISL1 and JMJD3 partner to alter the cardiac epigenome, instructing gene expression changes that drive cardiac differentiation.
- Subjects :
- 0301 basic medicine
Mef2
Jumonji Domain-Containing Histone Demethylases
Transcription, Genetic
Cellular differentiation
LIM-Homeodomain Proteins
Histones
03 medical and health sciences
Mice
Demethylase activity
Genetics
Animals
Humans
Regulation of gene expression
Genome
biology
Lysine
Myocardium
HEK 293 cells
Gene regulation, Chromatin and Epigenetics
Gene Expression Regulation, Developmental
Cell Differentiation
Mouse Embryonic Stem Cells
Epigenome
DNA Methylation
Embryonic stem cell
Molecular biology
Cell biology
030104 developmental biology
Enhancer Elements, Genetic
HEK293 Cells
Organ Specificity
biology.protein
cardiovascular system
NIH 3T3 Cells
Demethylase
Protein Binding
Transcription Factors
Subjects
Details
- ISSN :
- 13624962
- Volume :
- 44
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- Nucleic acids research
- Accession number :
- edsair.doi.dedup.....f2c0431ad039d2d06d9b2496a98fba65