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Molecular and Cellular Biology, March 2009, p. 1635-1648, Vol. 29, No. 6
0270-7306/09/$08.00+0     doi:10.1128/MCB.01735-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Evidence for a Bigenic Chromatin Subdomain in Regulation of the Fetal-to-Adult Hemoglobin Switch{triangledown} ,{dagger}

Hugues Beauchemin and Marie Trudel*

Institut de Recherches Cliniques de Montréal, Molecular Genetics and Development, Faculte de Medecine de l'Universite de Montreal, Montreal, Quebec, Canada

Received 12 November 2008/ Returned for modification 14 December 2008/ Accepted 20 December 2008

During development, human β-globin locus regulation undergoes two critical switches, the embryonic-to-fetal and fetal-to-adult hemoglobin switches. To define the role of the fetal A{gamma}-globin promoter in switching, human β-globin-YAC transgenic mice were produced with the A{gamma}-globin promoter replaced by the erythroid porphobilinogen deaminase (PBGD) promoter (PBGDA{gamma}-YAC). Activation of the stage-independent PBGDA{gamma}-globin strikingly stimulated native G{gamma}-globin expression at the fetal and adult stages, identifying a fetal gene pair or bigenic cooperative mechanism. This impaired fetal silencing severely suppressed both {delta}- and β-globin expression in PBGDA{gamma}-YAC mice from fetal to neonatal stages and altered kinetics and delayed switching of adult β-globin. This regulation evokes the two human globin switching patterns in the mouse. Both patterns of DNA demethylation and chromatin immunoprecipitation analysis correlated with gene activation and open chromatin. Locus control region (LCR) interactions detected by chromosome conformation capture revealed distinct spatial fetal and adult LCR bigenic subdomains. Since both intact fetal promoters are critical regulators of fetal silencing at the adult stage, we concluded that fetal genes are controlled as a bigenic subdomain rather than a gene-autonomous mechanism. Our study also provides evidence for LCR complex interaction with spatial fetal or adult bigenic functional subdomains as a niche for transcriptional activation and hemoglobin switching.

* Corresponding author. Mailing address: Molecular Genetics and Development, Institut de Recherches Cliniques de Montreal, 110 Ouest Avenue des Pins, Montreal, Quebec, Canada H2W 1R7. Phone: (514) 987-5712. Fax: (514) 987-5585. E-mail: trudelm{at}ircm.qc.ca

{triangledown} Published ahead of print on 29 December 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, March 2009, p. 1635-1648, Vol. 29, No. 6
0270-7306/09/$08.00+0     doi:10.1128/MCB.01735-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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