Abstract
Human embryonic stem cells (hESCs) could provide a major window into human developmental biology, because the differentiation methods from hESCs mimic human embryogenesis. We previously reported that the overexpression of hematopoietically expressed homeobox (HHEX) in the hESC-derived definitive endoderm (DE) cells markedly promotes hepatic specification. However, it remains unclear how HHEX functions in this process. To reveal the molecular mechanisms of hepatic specification by HHEX, we tried to identify the genes directly targeted by HHEX. We found that HHEX knockdown considerably enhanced the expression level of eomesodermin (EOMES). In addition, HHEX bound to the HHEX response element located in the first intron of EOMES. Loss-of-function assays of EOMES showed that the gene expression levels of hepatoblast markers were significantly upregulated, suggesting that EOMES has a negative role in hepatic specification from the DE cells. Furthermore, EOMES exerts its effects downstream of HHEX in hepatic specification from the DE cells. In conclusion, the present results suggest that HHEX promotes hepatic specification by repressing EOMES expression.
Highlights
The molecular mechanisms of liver development have been clarified by using model organisms such as chicks, Xenopus, zebrafish, and mice [1,2]
These results suggest that hepatoblast differentiation is prevented by hematopoietically expressed homeobox (HHEX) knockdown, demonstrating that HHEX plays an important role in hepatoblast differentiation from definitive endoderm (DE) cells
The percentage of AFPpositive cells or EOMES expression level was decreased or increased, respectively, by HHEX knockdown in the DE cells and in the cells starting to commit to hepatoblast (Fig. S2 in File S1)
Summary
The molecular mechanisms of liver development have been clarified by using model organisms such as chicks, Xenopus, zebrafish, and mice [1,2]. The use of differentiation models from human embryonic stem cells (hESCs) for studying human development might resolve these problems, because these differentiation methods mimic human embryogenesis [3]. Agarwal et al reported that the typical gene expression profiles observed in the differentiation model from hESCs are similar to those observed in fetal liver development [8]. We previously reported that CCAAT/enhancer binding protein-mediated regulation of TGF beta receptor 2 expression determines the hepatoblast fate decision by using a differentiation model from hESCs [9]. The use of differentiation models from hESCs, rather than the usual model organisms, would provide great opportunities to expand our understanding of the molecular mechanisms
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