Hepatic Erythropoietin Gene Regulation by GATA-4

Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2004; 279(4):2955-61. DOI: 10.1074/jbc.M310404200
Source: PubMed


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.

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    • "GATA6 expression has been reported in fetal and adult hepatocytes as well as adult cholangiocytes [20,21,24]. Reports on the predominant sites of GATA4 expression in the adult liver vary significantly and include hepatocytes [25], endothelial cells [20], and cholangiocytes [26]. The reasons for these disparities are unclear but might be rooted in the sensitivity and specificity of antibodies used for immunohistochemistry. "
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    ABSTRACT: GATA transcription factors and their Friend of Gata (FOG) cofactors control the development of diverse tissues. GATA4 and GATA6 are essential for the expansion of the embryonic liver bud, but their expression patterns and functions in the adult liver are unclear. We characterized the expression of GATA and FOG factors in whole mouse liver and purified hepatocytes. GATA4, GATA6, and FOG1 are the most prominently expressed family members in whole liver and hepatocytes. GATA4 chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq) identified 4409 occupied sites, associated with genes enriched in ontologies related to liver function, including lipid and glucose metabolism. However, hepatocyte-specific excision of Gata4 had little impact on gross liver architecture and function, even under conditions of regenerative stress, and, despite the large number of GATA4 occupied genes, resulted in relatively few changes in gene expression. To address possible redundancy between GATA4 and GATA6, both factors were conditionally excised. Surprisingly, combined Gata4,6 loss did not exacerbate the phenotype resulting from Gata4 loss alone. This points to the presence of an unusually robust transcriptional network in adult hepatocytes that ensures the maintenance of liver function.
    PLoS ONE 12/2013; 8(12):e83723. DOI:10.1371/journal.pone.0083723 · 3.23 Impact Factor
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    • "Epo expression is known to be upregulated by hypoxia through a transcription factor hypoxia-inducible factor-1 [22]. Other transcription factors like Wilms tumor protein, Wt1 [23] and GATA-4 [24] are also involved in Epo gene expression in the liver. So, in this light, although the molecular mechanism underlying Epo production in macrophages is not known, it is not an implausible finding. "
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    ABSTRACT: Background We describe a case of a fever of unknown etiology that was caused by a caseating tubercle granuloma which produced erythropoietin. To our knowledge, this is the first report of an erythropoietin- producing granuloma. Case presentation A 48-year-old Japanese man with a 5-year history of maintenance hemodialysis for diabetic nephropathy presented with an intermittent fever over a few months. During febrile periods he developed erythema nodosum on his legs. Computed tomography showed axillary lymph node enlargement and this was further corroborated by a gallium scan that revealed high gallium uptake in these nodes. A Mantoux test was positive and an interferongamma release assay for tuberculosis diagnosis was also positive. Lymph node tuberculosis was suspected and the patient underwent lymphadenectomy. Histological analysis of the lymph nodes revealed a caseating granuloma that showed positive results on an acid-fast bacteria stain and a Mycobacterium tuberculosis polymerase chain reaction test. After lymphadenectomy, however, the patient’s hemoglobin levels rapidly decreased from 144 to 105 g/L, and this was further compounded by a decrease in serum erythropoietin from 223 mIU/mL to 10.7 mIU/mL by postoperative day 21. We suspected the tubercle to be a source of the erythropoietin and this was further confirmed by in situ hybridization. Conclusions We report for the first time ectopic erythropoietin production by a tuberculous lymph node. Our observations are substantiated by a postoperative decline in his erythropoietin level and a clinical requirement for erythropoietin treatment.
    BMC Nephrology 04/2013; 14(1):91. DOI:10.1186/1471-2369-14-91 · 1.69 Impact Factor
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    • "Incidentally, GATA-4 was shown to be absent in hepatocytes that were isolated from normal mice and humans during the postnatal period (Dame et al. 2004, Divine et al. 2004). The absence of GATA-4 in hepatocytes during the postnatal period was also cited as the reason for the switch in the expression of the EPO gene from fetal hepatocytes to the adult kidney in mice and humans (Dame et al. 2004). The changes in concentrations of the proinflammatory cytokines (IL6) in the body during the postnatal period may therefore affect levels of either GATA-6 or FOG protein (1 and 2) in hepatocytes and the nature of the response being dependent on the type and strength of the input signal: the increase in GATA-6 with or without a decrease in FOG upregulating the transcription of HAMP; while the increase in concentration of FOG proteins with or without a decrease in GATA-6 concentrations downregulating the transcription of HAMP. "
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    ABSTRACT: Hepcidin is an antimicrobial peptide hormone involved in the metabolism of iron, encoded for by the HAMP gene mainly in hepatocytes. It's expressed at lower levels in other cells such as the macrophages. The mechanisms that determine tissue-specific expression of hepcidin remain unclear. GATA- and its co-factor Friend of GATA (FOG) modulate the tissue-specific transcription of other genes involved in the metabolism of iron. GATA proteins are group of evolutionary conserved transcriptional regulators that bind to the consensus motif -WGATAR- in the promoter. We characterized a 1.3 kb fragment of the 5'-flanking sequence of the HAMP gene in Huh7 cells, which express HAMP. Transfection of 5'-deletions of the HAMP promoter in Huh7 cells revealed two regions, -932/-878 and -155/-96, that when deleted decreased promoter activity. Using site-directed mutations in the HAMP promoter region -155/-96 we identified two subregions, -138/-125 and -103/-98, which when mutated suppressed promoter activity by 70 and 90% respectively. Site -103/-98 with a sequence -TTATCT- to which endogenous GATA proteins 4 and 6 bind and transactivate HAMP is a GATA-regulatory element (RE). Mutation of the GATA-RE abrogated binding of GATA proteins 4 and 6 to the promoter and blunted the GATA transactivation of HAMP. FOG proteins 1 and 2 suppressed the endogenous and exogenous GATA activation of the HAMP promoter. We concluded that the GATA-RE, -TTATCT- in the HAMP promoter region -103/-98 is crucial for the GATA-4 and GATA-6 driven transcription of hepcidin in Huh7 cells and that FOG proteins moderate the transcription by suppressing the GATA transactivation of HAMP.
    Journal of Molecular Endocrinology 12/2011; 47(3):299-313. DOI:10.1530/JME-11-0060 · 3.08 Impact Factor
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