Evidence for a bigenic chromatin subdomain in regulation of the fetal-to-adult hemoglobin switch.
During development, human beta-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 beta-globin-YAC transgenic mice were produced with the (A)gamma-globin promoter replaced by the erythroid porphobilinogen deaminase (PBGD) promoter (PBGD(A)gamma-YAC). Activation of the stage-independent PBGD(A)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 beta-globin expression in PBGD(A)gamma-YAC mice from fetal to neonatal stages and altered kinetics and delayed switching of adult beta-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.
Beauchemin
Hugues
H
Molecular Genetics and Development, Institut de Recherches Cliniques de Montreal, Faculte de Medecine de l'Universite de Montreal, Montreal, Quebec, Canada.
Trudel
Marie
M
D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D004622:Embryo, Mammalian / Q000378:metabolism; D005312:Fetal Blood / Q000378:metabolism; D047109:Fetal Development; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics / Q000378:metabolism; D019901:Locus Control Region; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism*; D055545:gamma-Globins / Q000235:genetics / Q000378:metabolism
D002843:Chromatin; D055544:beta-Globins; D055545:gamma-Globins; D005319:Fetal Hemoglobin; D011163:Hydroxymethylbilane Synthase