Silencing of human fetal globin expression is impaired in the absence of the adult beta-globin gene activator protein EKLF.
Globin genes are subject to tissue-specific and developmental stage-specific regulation. A switch from human fetal (gamma)-to adult (beta)-globin expression occurs within erythroid precursor cells of the adult lineage. Previously we and others showed by targeted gene disruption that the zinc finger gene, erythroid Krüppel-like factor (EKLF), is required for expression of the beta-globin gene in mice, presumably through interaction with a high-affinity binding site in the proximal promoter. To examine the role of EKLF in the developmental regulation of the human gamma-globin gene we interbred EKLF heterozygotes (+/-) with mice harboring a human beta-globin yeast artificial chromosome transgene. We find that in the absence of EKLF, while human beta-globin expression is dramatically reduced, gamma-globin transcripts are elevated approximately 5-fold. Impaired silencing of gamma-globin expression identifies EKLF as the first transcription factor participating quantitatively in the gamma-globin to beta-globin switch. Our findings are compatible with a competitive model of switching in which EKLF mediates an adult stage-specific interaction between the beta-globin gene promoter and the locus control region that excludes the gamma-globin gene.
Department of Hematology, Children's Hospital, Boston, MA, USA.
A C
AC
Perkins
K M
KM
Gaensler
S H
SH
Orkin
D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D015672:Erythroid Precursor Cells / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D005914:Globins / Q000235:genetics*; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D008954:Models, Biological; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D016335:Zinc Fingers / Q000502:physiology*
D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D014157:Transcription Factors; C080774:erythroid Kruppel-like factor; D005914:Globins; D005319:Fetal Hemoglobin