title: Mi2β is required for γ-globin gene silencing: temporal assembly of a GATA-1-FOG-1-Mi2 repressor complex in β-YAC transgenic mice.
abstract: Activation of γ-globin gene expression in adults is known to be therapeutic for sickle cell disease. Thus, it follows that the converse, alleviation of repression, would be equally effective, since the net result would be the same: an increase in fetal hemoglobin. A GATA-1-FOG-1-Mi2 repressor complex was recently demonstrated to be recruited to the -566 GATA motif of the (A)γ-globin gene. We show that Mi2β is essential for γ-globin gene silencing using Mi2β conditional knockout β-YAC transgenic mice. In addition, increased expression of (A)γ-globin was detected in adult blood from β-YAC transgenic mice containing a T>G HPFH point mutation at the -566 GATA silencer site. ChIP experiments demonstrated that GATA-1 is recruited to this silencer at day E16, followed by recruitment of FOG-1 and Mi2 at day E17 in wild-type β-YAC transgenic mice. Recruitment of the GATA-1-mediated repressor complex was disrupted by the -566 HPFH mutation at developmental stages when it normally binds. Our data suggest that a temporal repression mechanism is operative in the silencing of γ-globin gene expression and that either a trans-acting Mi2β knockout deletion mutation or the cis-acting -566 (A)γ-globin HPFH point mutation disrupts establishment of repression, resulting in continued γ-globin gene transcription during adult definitive erythropoiesis.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Flávia C
authors.initials: FC
authors.lastname: Costa
authors.forename: Halyna
authors.initials: H
authors.lastname: Fedosyuk
authors.forename: Allen M
authors.initials: AM
authors.lastname: Chazelle
authors.forename: Renee Y
authors.initials: RY
authors.lastname: Neades
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Peterson
mesh_terms: D000755:Anemia, Sickle Cell / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development; D004920:Erythropoiesis; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism; D055545:gamma-Globins / Q000235:genetics / Q000378:metabolism
chemical_list: D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; C107310:Zfpm1 protein, mouse; D055544:beta-Globins; D055545:gamma-Globins; D005319:Fetal Hemoglobin; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex