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Zrf1 controls mesoderm lineage genes and cardiomyocyte differentiation.

ABSTRACT: In the present study we addressed the function of the transcriptional activator Zrf1 in the generation of the 3 germ layers during in vitro development. Currently, Zrf1 is rather regarded as a factor that drives the expression of neuronal genes. Here, we have employed mouse embryonic stem cells and P19 cells to understand the role of Zrf1 in the generation of mesoderm-derived tissues like adipocytes, cartilage and heart. Our data shows that Zrf1 is essential for the transcriptional activation of genes that give rise to mesoderm and in particular heart development. In both, the mESC and P19 systems, we provide evidence that Zrf1 contributes to the generation of functional cardiomyocytes. We further demonstrate that Zrf1 binds to the transcription start sites (TSSs) of heart tissue-specific genes from the first and second heart field where it drives their temporal expression during differentiation. Taken together, we have identified Zrf1 as a novel regulator of the mesodermal lineage that might facilitate spatiotemporal expression of genes.

SUBMITTER: Kaymak A

PROVIDER: S-EPMC5176143 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Zrf1 controls mesoderm lineage genes and cardiomyocyte differentiation.

Kaymak Aysegül A Richly Holger H

Cell cycle (Georgetown, Tex.) 20161018 23

In the present study we addressed the function of the transcriptional activator Zrf1 in the generation of the 3 germ layers during in vitro development. Currently, Zrf1 is rather regarded as a factor that drives the expression of neuronal genes. Here, we have employed mouse embryonic stem cells and P19 cells to understand the role of Zrf1 in the generation of mesoderm-derived tissues like adipocytes, cartilage and heart. Our data shows that Zrf1 is essential for the transcriptional activation of ...[more]

PMID: 27754813

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Project description:Differentiation of cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) is critically dependent upon the regulation of the Wnt signaling pathway. The mechanisms remain unclear with regard to the dose and timing of each differentiation inducer, and the interaction of the inducers that regulate the Wnt in mesendoderm specification to cardiac mesoderm. Consequently, it remains far from optimal in differentiation efficiency and consistency from hiPSC lines to CMs. Here, we have carefully deciphered the role of Wnt signaling pathway manipulation on mesoderm specification in a dosage and time dependent manner. To examine the hypothesis of that fate specification of hiPSC-CMs differentiation is dictated by temporal and spatial factors that regulate Wnt, we evaluate hiPSC-CM differentiation with: (1) two-phase modulation of Wnt, (2) dosage variant of GSK3β inhibitors, (3) treatment with insulin, and (4) 3-dimentional suspension culture environment on iPSC-CM differentiation. The results highlight the importance of mesendoderm specification to cardiac mesoderm, which needs precisely regulation of Wnt in a dosage dependent and temporal on/off manner. This temporal regulation dictates the final efficiency and purity of derived cardiomyocytes. After the initial activation of Wnt signaling pathway to generate mesendoderm, the maintenance of Wnt signaling at an appropriate dose is critical to direct the cell fate into cardiac mesoderm. Otherwise, lower Wnt signals lead to definitive endoderm and higher Wnt signals induce presomitic mesoderm differentiation. The precisely specification of cardiac mesoderm results in not only greater than 90% of cTnT+ cardiomyocytes but also high cardiomyocytes yield under both monolayer and suspension culture conditions. Thus, the current findings provide critical insights to decipher the temporal mechanism of Wnt activation in regulation of hiPSC-CMs differentiation, and more importantly provide the guidelines for the consistent and high-yield and high-quality hiPSC-CMs production in cardiovascular research.

Dataset Information

Zrf1 controls mesoderm lineage genes and cardiomyocyte differentiation.

Publications

Zrf1 controls mesoderm lineage genes and cardiomyocyte differentiation.

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