Key points are not available for this paper at this time.
Erythropoietin production switches from fetal liver to adult kidney during development. GATA transcription factors 2 and 3 could be involved in modulating this switch, because they were shown to negatively regulate erythropoietin gene transcription through a promoter proximal GATA site. Herein, we analyzed the role of several GATA factors in the regulation of the erythropoietin gene in human liver and in hepatoma cells. Although GATA-3 expression in hepatocytes increases during human development, erythropoietin mRNA accumulation is unaltered in mutant mice lacking GATA-3. We found that GATA-2, -3, -4, and -6 are all expressed in human hepatocytes and that GATA-4 exhibits the most prominent Epo promoter binding activity in vitro and in vivo. Inhibition of GATA-4 expression by RNA interference leads to a dramatic reduction in Epo gene transcription in Hep3B cells. Moreover, GATA-4 expression is high and limited to hepatocytes in the fetal liver, whereas GATA-4 expression in the adult liver is low and restricted to epithelial cells surrounding the biliary ducts. Thus, GATA-4 is critical for transcription of the Epo gene in hepatocytes and may contribute to the switch in the site of Epo gene expression from the fetal liver to the adult kidney. Erythropoietin production switches from fetal liver to adult kidney during development. GATA transcription factors 2 and 3 could be involved in modulating this switch, because they were shown to negatively regulate erythropoietin gene transcription through a promoter proximal GATA site. Herein, we analyzed the role of several GATA factors in the regulation of the erythropoietin gene in human liver and in hepatoma cells. Although GATA-3 expression in hepatocytes increases during human development, erythropoietin mRNA accumulation is unaltered in mutant mice lacking GATA-3. We found that GATA-2, -3, -4, and -6 are all expressed in human hepatocytes and that GATA-4 exhibits the most prominent Epo promoter binding activity in vitro and in vivo. Inhibition of GATA-4 expression by RNA interference leads to a dramatic reduction in Epo gene transcription in Hep3B cells. Moreover, GATA-4 expression is high and limited to hepatocytes in the fetal liver, whereas GATA-4 expression in the adult liver is low and restricted to epithelial cells surrounding the biliary ducts. Thus, GATA-4 is critical for transcription of the Epo gene in hepatocytes and may contribute to the switch in the site of Epo gene expression from the fetal liver to the adult kidney. The erythropoietin (Epo) 1The abbreviations used are: Epo, erythropoietin; HIF-1, hypoxiainducible factor-1; GA, gestational age; pc, post conception; E, embryonic day(s); RT, reverse transcription; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; EMSA, electrophoretic mobility shift assay; ChIP, chromatin immunoprecipitation; siRNA, small interference RNA. gene is expressed in a developmental stage and tissue-specific manner in various organs, including the kidney, liver, bone marrow, CNS, intestine, testis, and uterus (1.Ebert B.L. Bunn H.F. Blood. 1999; 94: 1864-1877Crossref PubMed Google Scholar, 2.Masuda S. Nagao M. Sasaki R. Int. J. Hematol. 1999; 70: 1-6PubMed Google Scholar, 3.Tan C.C. Eckardt K.U. Firth J.D. Ratcliffe P.J. Am. J. Physiol. 1992; 263: F474-F481Crossref PubMed Google Scholar). An interesting aspect is the developmental switch of the primary Epo production site from the fetal liver to the adult kidney. This switch is characterized by species-specific differences in the time of the onset (4.Dame C. Fahnenstich H. Freitag P. Hofmann D. Abdul-Nour T. Bartmann P. Fandrey J. Blood. 1998; 92: 3218-3225Crossref PubMed Google Scholar, 5.Peschle C. Marone G. Genovese A. Cillo C. Magli C. Condorelli M. Life Sci. 1975; 17: 1325-1330Crossref PubMed Scopus (18) Google Scholar, 6.Zanjani E.D. Poster J. Burlington H. Mann L.I. Wasserman L.R. J. Lab. Clin. Med. 1977; 89: 640-644PubMed Google Scholar, 7.Lim G.B. Jeyaseelan K. Wintour E.M. Blood. 1994; 84: 460-466Crossref PubMed Google Scholar, 8.Moritz K.M. Lim G.B. Wintour E.M. Am. J. Physiol. 1997; 273: R1829-R1844PubMed Google Scholar, 9.Eckhardt K.U. Ratcliffe P.J. Tan C.C. Bauer C. Kurtz A. J. Clin. Invest. 1992; 89: 753-760Crossref PubMed Scopus (101) Google Scholar, 10.Bondurant M.C. Koury M.J. Koury S.T. Semenza G. Semin. Hematol. 1991; 28: 20-25PubMed Google Scholar, 11.Klemcke H.G. Vallet J.L. Christenson R.K. Pearson P.L. Anim. Reprod. 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The of the as were DNA and the RNA and proteins were as S.H. K. J. 2002; PubMed Google Scholar). DNA and in of by of DNA in a of of of the of DNA were with 2 of of and of to a of The were Epo 5′-flanking 5′ 3′ 5′ were in the and in The and Epo and were for of in The were and were by from Hep3B cells were and analyzed by as by K.M. K. K. P.P. Engel J.D. J. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar, K.M. S.H. A. M. J. PubMed Scopus Google for the GATA transcription factors as as as for and RNA used to GATA-4 in Hep3B cells. The were of a human promoter as G. C. F. Y. W.C. Proc. Natl. Acad. Sci. U. S. A. 2002; PubMed Scopus Google Scholar). different to of in the 5′ of the GATA-4 sequence were into were with the human data to homology to DNA were for the the sequence to the reverse by a were to the of the and for and sites were to the 5′ and 3′ of the The have the The and reverse were and into the and sites in Hep3B cells were a of to in to to fetal were to the of of and of DNA after fetal and were The reduction of GATA-4 expression by analyzed by and were and for in of and in human hepatoma cell in with fetal and in were in a with and were to the cells for and of GATA-3 in Epo during of the have shown that GATA-3 negatively Epo gene transcription through a promoter proximal in vitro (23.Weiss M.J. Orkin S.H. Exp. Hematol. 1995; 23: 99-107PubMed Google Scholar). GATA-3 is involved in the switch of Epo gene transcription from the fetal liver to the adult kidney, we GATA-3 expression in human liver different developmental revealed that GATA-3 is expressed in hematopoietic cells and in hepatocytes GATA-1 is expressed in hematopoietic cells and of hematopoietic activity in the fetal liver as shown C. M.C. Fandrey J. Freitag P. G. R.D. J. Br. J. Haematol. 2002; PubMed Scopus Google Scholar). the of GATA-3 we have the to of hematopoietic activity in the shown in and GATA-1 expression in liver after expression of GATA-3 The expression pattern of GATA-3 and Epo during in the liver and C. Fahnenstich H. Freitag P. Hofmann D. Abdul-Nour T. Bartmann P. Fandrey J. Blood. 1998; 92: 3218-3225Crossref PubMed Google to the role of GATA-3 in the switch from liver to Epo gene expression in fetal mice for GATA-3 and Epo expression and pc, that the switch from liver to Epo in mice Epo gene expression is by the of GATA-3. and Epo of GATA in and data that expression of GATA-2 in human hepatocytes during development, M. C. G. and J. to the expression pattern of all six GATA transcription factors in Hep3B cells. and indicate that Hep3B cells GATA-2, -3, -4, and GATA-1 and GATA-2, -3, -4, and -6 with GATA binding sites in the Epo we with from Hep3B cells are two GATA binding sites in the Epo promoter region, and the to the transcription site S. Lin R. Chen F. E. Proc. Natl. Acad. Sci. U. S. A. 82: PubMed Scopus Google Scholar). in vitro binding of the Epo promoter on the GATA binding site and in cells in which GATA-1, -2, -3 were S. Yamamoto M. Miura Y. Blood. 1997; 89: 1430-1439Crossref PubMed Google Scholar, 21.Imagawa S. Suzuki N. Ohmine K. Obara N. Mukai H.Y. Ozawa K. Yamamoto M. Nagasawa T. Int. J. Hematol. 2002; 75: 376-381Crossref PubMed Scopus (21) Google Scholar). of the the GATA site with cell from Hep3B cells leads to the of several all of these in after with after with a mutant by a a and a that of these a GATA site. We used for GATA-2 and -3 to these proteins bind to the GATA site. to the to with GATA-2 GATA-3 the the and is by with and of is by with and the which of the GATA factors with the Epo gene in hepatocytes in we in Hep3B cells these for GATA-2, -3, -4, and RNA the and the transcription factors and were The to the Epo promoter and as a in this are several binding sites in the Epo and is to with GATA factors M. Orkin S.H. Mol. Cell. Biol. 1995; PubMed Scopus Google Scholar). The of GATA and binding sites to the Epo transcription site are shown in a we analyzed the binding of all these factors to the human The data indicate that all of the GATA and be to the Epo promoter in GATA-4 to binding activity the GATA bind to the Epo gene to the Epo gene to the that the of GATA-2, -3, -4, and are for the Epo promoter of GATA-4 RNA on Epo in Hep3B used RNA interference to expression of GATA-4 in Hep3B cells and analyzed the on Epo gene expression by We two constructs two and Hep3B cells were with the two after RNA and proteins were and analyzed by The shown in that GATA-4 expression by RNA interference of the constructs in with the cells Epo mRNA in the cells expressed in the cells. The in that GATA-4 were in the cells. The that expressed in the and cells that the reduction of GATA-4 by RNA interference The to of GATA-4 expression a that with the in gene expression in these cells. We analyzed the expression of GATA factors in and Hep3B cells The that the of GATA-4 in the expression of GATA-2, -3, -6 in these cells. of GATA-4 and -6 in and for GATA-4 and -6 in human kidney, and that GATA-4 is expressed in the fetal liver of GATA-4 in the fetal adult kidney and CNS, two the Epo is low We analyzed the expression of GATA-4 in human fetal and adult liver by and GATA-4 is expressed in different cell during development. in development, GATA-4 is expressed in hepatocytes and cells. of these cells of which are to the Epo gene the adult liver GATA-4 is restricted to epithelial cells of the biliary of and on of GATA-4 in expression of Epo is by and by we were to these the expression of GATA-4 in hepatic cells. these we used of Hep3B cells. is a hepatoma cell which for Epo gene regulation. We were in examining expression of GATA-4 in these cells as shown in GATA-4 is expressed in and in to its expression is by is in GATA-4 expression in response to characterized of of Epo is the by cis-acting DNA elements within the 5′ promoter and the Epo 3′ enhancer (1.Ebert B.L. Bunn H.F. Blood. 1999; 94: 1864-1877Crossref PubMed Google Scholar). aspect in the tissue-specific regulation of the Epo gene is the switch of the Epo production site from the fetal liver to the kidney. from in that this is regulated E.D. Blood. 70: PubMed Google Scholar). that GATA-2 and GATA-3 bind to the Epo promoter and Epo gene expression in that these two regulatory proteins could be involved in Epo gene expression in the liver and in the is shown that hepatic expression of GATA-3 increases during S. Yamamoto M. Miura Y. Blood. 1997; 89: 1430-1439Crossref PubMed Google Scholar, 21.Imagawa S. Suzuki N. Ohmine K. Obara N. Mukai H.Y. Ozawa K. Yamamoto M. Nagasawa T. Int. J. Hematol. 2002; 75: 376-381Crossref PubMed Scopus (21) Google that GATA-3 as a of Epo gene transcription in cell GATA-3 be involved in the switch of the primary Epo production site from the fetal liver to the adult kidney. data from mice that GATA-3 is critical for the developmental regulation of Epo gene expression in the murine be in different is that the Epo gene is regulated by different GATA factors in mice which could species-specific differences in the onset and of the switch (4.Dame C. Fahnenstich H. Freitag P. Hofmann D. Abdul-Nour T. Bartmann P. Fandrey J. Blood. 1998; 92: 3218-3225Crossref PubMed Google Scholar, 8.Moritz K.M. Lim G.B. Wintour E.M. Am. J. Physiol. 1997; 273: R1829-R1844PubMed Google Scholar, 10.Bondurant M.C. Koury M.J. Koury S.T. Semenza G. Semin. Hematol. 1991; 28: 20-25PubMed Google Scholar). is that as activity for the of GATA-3. GATA factors in the regulation of Epo gene expression during liver development, we analyzed the expression of all GATA factors in Hep3B cells. Hep3B and are hepatoma cell with to fetal hepatocytes and are as for hepatic Epo gene regulation Bunn H.F. Proc. Natl. Acad. Sci. U. S. A. 84: PubMed Scopus Google Scholar). and that GATA-2, -3, -4, and -6 are expressed in Hep3B cells. the that all of these proteins with the Epo gene in vivo. data are with from S. Yamamoto M. Miura Y. Blood. 1997; 89: 1430-1439Crossref PubMed Google Scholar, 21.Imagawa S. Suzuki N. Ohmine K. Obara N. Mukai H.Y. Ozawa K. Yamamoto M. Nagasawa T. Int. J. Hematol. 2002; 75: 376-381Crossref PubMed Scopus (21) Google binding of GATA-2 and -3 to the GATA site in the Epo promoter from cells in which GATA-2 -3 were both and that GATA-4 interacts with the GATA sites in the Epo promoter and exhibits the most prominent Epo promoter binding activity the GATA The for GATA-4 in the could indicate that most of the cells have GATA-4 the whereas GATA-2, -3, and -6 bind to the Epo promoter in a of cells. This be with because is that the for GATA-2, -3, and -6 may be as in the as the for The from the GATA-4 RNA interference that GATA-4 a critical role in Epo gene regulation in Hep3B cells. This activity be by GATA factors in Hep3B including by Lin D. M. Mol. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google that GATA-4 with hepatic nuclear to the chromatin the gene GATA factors as critical of chromatin to D.L. C. Weiss M.J. Mol. Cell. Biol. 23: PubMed Scopus Google Scholar). The on the regulation of the Epo the of RNA with the Epo promoter that the chromatin is and to transcription factors of this is interesting to that a with activity T. Nature. PubMed Scopus Google Scholar, V. Y. Cell. Full Text Full Text PDF PubMed Scopus Google be to the Epo promoter is to with of the the Epo 3′ enhancer B.L. Bunn H.F. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar). The data with the expression of GATA-4 in the fetal and adult human liver that GATA-4 in the switch of the primary Epo production site from fetal liver to adult kidney. The expression of GATA-4 in hepatocytes that of Epo and is restricted to developmental GATA-4 is in epithelial cells surrounding the biliary ducts. are with the expression pattern of GATA-4 in the murine liver P. 1998; PubMed Google Scholar). The data that GATA-4 is critical for Epo gene expression in the fetal liver and that the of GATA-4 expression in adult hepatocytes to the of Epo gene GATA-4 to be involved in of Epo gene expression that are mediated by and Ferla K. Reimann C. Jelkmann W. Hellwig-Burgel T. FASEB J. 2002; 16: 1811-1813Crossref PubMed Google Scholar, B.L. Bunn H.F. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar). we that GATA-4 to the Epo promoter in a tissue-specific manner and interacts with to the Epo gene promoter to transcription factors and RNA the role of GATA-4 in chromatin the enhancer Lin D. M. Mol. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). have GATA factors in the of chromatin GATA-1, to with T. R. M. Orkin S.H. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google to be for the of the gene J.A. M.E. Proc. Natl. Acad. Sci. U. S. A. 2002; PubMed Scopus Google Scholar). GATA-2 shown to with transcription of Y. M. S. F. T. Y. M. H. Blood. 2001; PubMed Scopus Google Scholar). We that GATA-4 to the Epo promoter in fetal hepatocytes and to expression of the the adult the of GATA-4 in with the of GATA-2 with the Epo may to the of a chromatin and of Epo gene the of GATA-4 is and GATA mediate of the Epo gene in in which GATA-4 is kidney. We of for We F. from for with GATA-2 and -3 used for were by of We D. of for critical of the
Dame et al. (Thu,) studied this question.