|
|
Blood, 15 December 2006, Vol. 108, No. 13, pp. 4237-4245.
Prepublished online as a Blood First Edition Paper on August 10, 2006; DOI 10.1182/blood-2005-07-027037.
 Previous Article | Table of Contents | Next Article 
RED CELLS
Cis and trans regulation of hepcidin expression by upstream stimulatory factor
Henry K. Bayele,
Harry McArdle, and
Surjit K.S. Srai
From the Department of Biochemistry and Molecular Biology, University College London; and The Rowett Research Institute, Aberdeen, United Kingdom.
Hepcidin is the presumed negative regulator of systemic iron levels; its expression is induced in iron overload, infection, and inflammation, and by cytokines, but is suppressed in hypoxia and anemia. Although the gene is exquisitely sensitive to changes in iron status in vivo, its mRNA is devoid of prototypical iron-response elements, and it is therefore not obvious how it may be regulated by iron flux. The multiplicity of effectors of its expression also suggests that the transcriptional circuitry controlling the gene may be very complex indeed. In delineating enhancer elements within both the human and mouse hepcidin gene promoters, we show here that members of the basic helix-loop-helix leucine zipper (bHLH-ZIP) family of transcriptional regulators control hepcidin expression. The upstream stimulatory factor 2 (USF2), previously linked to hepcidin through gene ablation in inbred mice, appears to exert a polar or cis-acting effect, while USF1 may act in trans to control hepcidin expression. In mice, we found variation in expression of both hepcidin genes, driven by these transcription factors. In addition, c-Myc and Max synergize to control the expression of this hormone, supporting previous findings for the role of this couple in regulating iron metabolism. Transcriptional activation by both USF1/USF2 and c-Myc/Max heterodimers occurs through E-boxes within the promoter. Site-directed mutagenesis of these elements rendered the promoter unresponsive to USF1/USF2 or c-Myc/Max. Dominant-negative mutants of USF1 and USF2 reciprocally attenuated promoter transactivation by both wild-type USF1 and USF2. Promoter occupancy by the transcription factors was confirmed by DNA-binding and chromatin immunoprecipitation assays. Taken together, it would appear that synergy between these members of the bHLH-ZIP family of transcriptional regulators may subserve an important role in iron metabolism as well as other pathways in which hepcidin may be involved.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
H. K. Bayele and S. K. S. Srai
Genetic variation in hepcidin expression and its implications for phenotypic differences in iron metabolism
Haematologica,
September 1, 2009;
94(9):
1185 - 1188.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Andreani, F. C. Radio, M. Testi, C. De Bernardo, M. Troiano, S. Majore, P. Bertucci, P. Polchi, R. Rosati, and P. Grammatico
Association of hepcidin promoter c.-582 A>G variant and iron overload in thalassemia major
Haematologica,
September 1, 2009;
94(9):
1293 - 1296.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Matak, T. B. Chaston, B. Chung, S. K. Srai, A. T. McKie, and P. A. Sharp
Activated macrophages induce hepcidin expression in HuH7 hepatoma cells
Haematologica,
June 1, 2009;
94(6):
773 - 780.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Kautz, D. Meynard, A. Monnier, V. Darnaud, R. Bouvet, R.-H. Wang, C. Deng, S. Vaulont, J. Mosser, H. Coppin, et al.
Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver
Blood,
August 15, 2008;
112(4):
1503 - 1509.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. C. Andrews
Forging a field: the golden age of iron biology
Blood,
July 15, 2008;
112(2):
219 - 230.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. K. Bayele, C. Peyssonnaux, A. Giatromanolaki, W. W. Arrais-Silva, H. S. Mohamed, H. Collins, S. Giorgio, M. Koukourakis, R. S. Johnson, J. M. Blackwell, et al.
HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA forming microsatellite
Blood,
October 15, 2007;
110(8):
3039 - 3048.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
