HHEX Promotes Hepatic-lineage Specification Through the Negative Regulation of Eomesodermin

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 Mar 22

PMID 24651531

Citations 15

Authors

Hitoshi Watanabe

Kazuo Takayama

Mitsuru Inamura

Masashi Tachibana

Natsumi Mimura

Kazufumi Katayama

Katsuhisa Tashiro

Yasuhito Nagamoto

Fuminori Sakurai

Kenji Kawabata

Miho Kusuda Furue

Hiroyuki Mizuguchi

Affiliations

Soon will be listed here.

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.

Citing Articles

Gender-specific genetic influence of rs1111875 on diabetes risk: Insights from the Taiwan biobank study.

Chiang C, Chou Y, Huang C, Lu W, Liaw Y J Diabetes Investig. 2024; 16(1):36-42.

PMID: 39555857 PMC: 11693539. DOI: 10.1111/jdi.14359.

Embryonic Amoxicillin Exposure Has Limited Impact on Liver Development but Increases Susceptibility to NAFLD in Zebrafish Larvae.

Gao P, Chang C, Liang J, Du F, Zhang R Int J Mol Sci. 2024; 25(5).

PMID: 38473993 PMC: 10931932. DOI: 10.3390/ijms25052744.

The Haematopoietically-expressed homeobox transcription factor: roles in development, physiology and disease.

Jackson J, Nutt S, McCormack M Front Immunol. 2023; 14:1197490.

PMID: 37398663 PMC: 10313424. DOI: 10.3389/fimmu.2023.1197490.

Elucidation of HHEX in pancreatic endoderm differentiation using a human iPSC differentiation model.

Ito R, Kimura A, Hirose Y, Hatano Y, Mima A, Mae S Sci Rep. 2023; 13(1):8659.

PMID: 37248264 PMC: 10227077. DOI: 10.1038/s41598-023-35875-1.

Integrative network analysis of circular RNAs reveals regulatory mechanisms for hepatic specification of human iPSC-derived endoderm.

Bai F, Duan J, Yang D, Lai X, Zhu X, He X Stem Cell Res Ther. 2022; 13(1):468.

PMID: 36076262 PMC: 9461288. DOI: 10.1186/s13287-022-03160-z.

References

Takayama K, Kawabata K, Nagamoto Y, Inamura M, Ohashi K, Okuno H . CCAAT/enhancer binding protein-mediated regulation of TGFβ receptor 2 expression determines the hepatoblast fate decision. Development. 2013; 141(1):91-100. DOI: 10.1242/dev.103168. View

Nagamoto Y, Tashiro K, Takayama K, Ohashi K, Kawabata K, Sakurai F . The promotion of hepatic maturation of human pluripotent stem cells in 3D co-culture using type I collagen and Swiss 3T3 cell sheets. Biomaterials. 2012; 33(18):4526-34. DOI: 10.1016/j.biomaterials.2012.03.011. View

Bogue C, Ganea G, Sturm E, Ianucci R, Jacobs H . Hex expression suggests a role in the development and function of organs derived from foregut endoderm. Dev Dyn. 2000; 219(1):84-9. DOI: 10.1002/1097-0177(2000)9999:9999<::AID-DVDY1028>3.0.CO;2-5. View

Morrison G, Oikonomopoulou I, Portero Migueles R, Soneji S, Livigni A, Enver T . Anterior definitive endoderm from ESCs reveals a role for FGF signaling. Cell Stem Cell. 2008; 3(4):402-15. DOI: 10.1016/j.stem.2008.07.021. View

Noy P, Williams H, Sawasdichai A, Gaston K, Jayaraman P . PRH/Hhex controls cell survival through coordinate transcriptional regulation of vascular endothelial growth factor signaling. Mol Cell Biol. 2010; 30(9):2120-34. PMC: 2863580. DOI: 10.1128/MCB.01511-09. View

Takayama K, Inamura M, Kawabata K, Sugawara M, Kikuchi K, Higuchi M . Generation of metabolically functioning hepatocytes from human pluripotent stem cells by FOXA2 and HNF1α transduction. J Hepatol. 2012; 57(3):628-36. DOI: 10.1016/j.jhep.2012.04.038. View

Si-Tayeb K, Lemaigre F, Duncan S . Organogenesis and development of the liver. Dev Cell. 2010; 18(2):175-89. DOI: 10.1016/j.devcel.2010.01.011. View

Kubo A, Kim Y, Irion S, Kasuda S, Takeuchi M, Ohashi K . The homeobox gene Hex regulates hepatocyte differentiation from embryonic stem cell-derived endoderm. Hepatology. 2010; 51(2):633-41. DOI: 10.1002/hep.23293. View

Takayama K, Inamura M, Kawabata K, Tashiro K, Katayama K, Sakurai F . Efficient and directive generation of two distinct endoderm lineages from human ESCs and iPSCs by differentiation stage-specific SOX17 transduction. PLoS One. 2011; 6(7):e21780. PMC: 3131299. DOI: 10.1371/journal.pone.0021780. View

10.

Agarwal S, Holton K, Lanza R . Efficient differentiation of functional hepatocytes from human embryonic stem cells. Stem Cells. 2008; 26(5):1117-27. DOI: 10.1634/stemcells.2007-1102. View

11.

Takayama K, Nagamoto Y, Mimura N, Tashiro K, Sakurai F, Tachibana M . Long-term self-renewal of human ES/iPS-derived hepatoblast-like cells on human laminin 111-coated dishes. Stem Cell Reports. 2013; 1(4):322-35. PMC: 3849256. DOI: 10.1016/j.stemcr.2013.08.006. View

12.

Tanaka H, Yamamoto T, Ban T, Satoh S, Tanaka T, Shimoda M . Hex stimulates the hepatocyte nuclear factor 1alpha-mediated activation of transcription. Arch Biochem Biophys. 2005; 442(1):117-24. DOI: 10.1016/j.abb.2005.08.001. View

13.

Swingler T, Bess K, Yao J, Stifani S, Jayaraman P . The proline-rich homeodomain protein recruits members of the Groucho/Transducin-like enhancer of split protein family to co-repress transcription in hematopoietic cells. J Biol Chem. 2004; 279(33):34938-47. DOI: 10.1074/jbc.M404488200. View

14.

DAmour K, Bang A, Eliazer S, Kelly O, Agulnick A, Smart N . Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol. 2006; 24(11):1392-401. DOI: 10.1038/nbt1259. View

15.

Crompton M, Bartlett T, Macgregor A, Manfioletti G, Buratti E, Giancotti V . Identification of a novel vertebrate homeobox gene expressed in haematopoietic cells. Nucleic Acids Res. 1992; 20(21):5661-7. PMC: 334400. DOI: 10.1093/nar/20.21.5661. View

16.

Takayama K, Kawabata K, Nagamoto Y, Kishimoto K, Tashiro K, Sakurai F . 3D spheroid culture of hESC/hiPSC-derived hepatocyte-like cells for drug toxicity testing. Biomaterials. 2012; 34(7):1781-9. DOI: 10.1016/j.biomaterials.2012.11.029. View

17.

Si-Tayeb K, Noto F, Nagaoka M, Li J, Battle M, Duris C . Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology. 2009; 51(1):297-305. PMC: 2946078. DOI: 10.1002/hep.23354. View

18.

Bort R, Martinez-Barbera J, Beddington R, Zaret K . Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas. Development. 2004; 131(4):797-806. DOI: 10.1242/dev.00965. View

19.

Thomson J, Itskovitz-Eldor J, Shapiro S, Waknitz M, Swiergiel J, Marshall V . Embryonic stem cell lines derived from human blastocysts. Science. 1998; 282(5391):1145-7. DOI: 10.1126/science.282.5391.1145. View

20.

Guiral M, Bess K, Goodwin G, Jayaraman P . PRH represses transcription in hematopoietic cells by at least two independent mechanisms. J Biol Chem. 2000; 276(4):2961-70. DOI: 10.1074/jbc.M004948200. View