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.
    Full-text · Article · Dec 2013 · PLoS ONE
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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.
    Full-text · Article · Apr 2013 · BMC Nephrology
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    • "GATA-4 is expressed exclusively in hepatocytes and binds strongly to this GATA motif, enhancing Epo expression (Dame et al. 2004). The marked reduction in expression of hepatic GATA-4 following birth is likely an important contributor to the switch in Epo production from liver to kidney (Dame et al. 2004). A crucial 3 0 enhancer (Beck et al. 1991;Pugh et al. 1991;Semenza et al. 1991b; Semenza andWang 1992) binds to two transcription factors, hypoxia-inducible factor 1 (HIF) and the nuclear receptor HNF-4. "
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    ABSTRACT: During the past century, few proteins have matched erythropoietin (Epo) in capturing the imagination of physiologists, molecular biologists, and, more recently, physicians and patients. Its appeal rests on its commanding role as the premier erythroid cytokine, the elegant mechanism underlying the regulation of its gene, and its remarkable impact as a therapeutic agent, arguably the most successful drug spawned by the revolution in recombinant DNA technology. This concise review will begin with a synopsis of the colorful history of this protein, culminating in its purification and molecular cloning. It then covers in more detail the contemporary understanding of Epo's physiology as well as its structure and interaction with its receptor. A major part of this article focuses on the regulation of the Epo gene and the discovery of HIF, a transcription factor that plays a cardinal role in molecular adaptation to hypoxia. In the concluding section, a synopsis of Epo's role in disorders of red blood cell production will be followed by an assessment of the remarkable impact of Epo therapy in the treatment of anemias, as well as concerns that provide a strong impetus for the development of even safer and more effective treatment.
    Preview · Article · Mar 2013 · Cold Spring Harbor Perspectives in Medicine
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