Hepatic erythropoietin gene regulation by GATA-4.
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.
Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610, USA.
Christof
C
Dame
Martha C
MC
Sola
Kim-Chew
KC
Lim
Kelly M
KM
Leach
Joachim
J
Fandrey
Yaluan
Y
Ma
Gisela
G
Knöpfle
James Douglas
JD
Engel
Jörg
J
Bungert
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004921:Erythropoietin / Q000235:genetics* / Q000378:metabolism; D050989:GATA2 Transcription Factor; D050990:GATA3 Transcription Factor; D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; C494712:Gata2 protein, mouse; C494748:Gata3 protein, mouse; C484171:Gata4 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D004921:Erythropoietin