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J. Biol. Chem., Vol. 276, Issue 45, 41700-41709, November 9, 2001

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Cooperation and Competition between the Binding of COUP-TFII and NF-Y on Human - and -Globin Gene Promoters^*

Chiara Liberati, Maria Rosaria Cera, Paola Secco^§, Claudio Santoro^§, Roberto Mantovani^¶, Sergio Ottolenghi, and Antonella Ronchi

From the  Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, 20126 Milano, Italy, ^§ Dipartimento di Scienze Mediche, Università del Piemonte Orientale A. Avogadro, 28100 Novara, Italy, and ^¶ Dipartimento di Biologia Animale, Università di Modena, 41100 Modena, Italy

The nuclear receptor COUP-TFII was recently shown to bind to the promoter of the - and -globin genes and was identified as the nuclear factor NF-E3. Transgenic experiments and genetic evidence from humans affected with hereditary persistence of fetal hemoglobin suggest that NF-E3 may be a repressor of adult  and  expression. We show that, on the -promoter, recombinant COUP-TFII binds to two sites, the more downstream of which overlaps with an NF-Y binding CCAAT box. Binding occurs efficiently to either the 5' or the 3' COUP-TFII site but not to both sites simultaneously. However, adding recombinant NF-Y induces the formation of a stable COUP-TFII·NF-Y-promoter complex at concentrations of COUP-TFII that would not give significant binding in the absence of NF-Y. Mutations of the promoter indicate that COUP-TFII cooperates with NF-Y when bound to the 5' site, whereas binding at the 3' site is mutually exclusive. Likewise, in the -promoter, COUP-TFII binds to a site overlapping the distal member of a duplicated CCAAT box, competing with NF-Y binding. Transfections in K562 cells show that both the mutation of the 5' COUP-TFII or of the NF-Y site on the -promoter decrease the activity of a luciferase reporter; the mutation of the 3' COUP-TFII site has little effect. These results, together with transgenic experiments suggesting a repressive activity of COUP-TFII on the -promoter and the observation that, on the 3' site, COUP-TFII and NF-Y binding is mutually exclusive, suggest that COUP-TFII may exert different effects on  transcription depending on whether it binds to the 5' or to the 3' site. At the 5' site, COUP-TFII might cooperate with NF-Y, forming a stable complex, and stimulate transcription; at the 3' site, COUP-TFII might compete for binding with NF-Y and, directly or indirectly, decrease gene activity.

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