The role of EKLF in human β-globin gene competition.
Genes & Development , Volume 10 p. 2894- 2902
We have investigated the role of erythroid Kruppel-like factor (EKLF) in expression of the human beta-globin genes in compound EKLF knockout/human beta-locus transgenic mice. EKLF affects only the adult mouse beta-globin genes in homozygous knockout mice; heterozygous mice are unaffected. Here we show that EKLF knockout mice express the human epsilon and gamma-globin genes normally in embryonic red cells. However, fetal liver erythropoiesis, which is marked by a period of gamma- and beta-gene competition in which the genes are alternately transcribed, exhibits an altered ratio of gamma- to beta-gene transcription. EKLF heterozygous fetal livers display a decrease in the number of transcriptionally active beta genes with a reciprocal increase in the number of transcriptionally active gamma genes. beta-Gene transcription is absent in homozygous knockout fetuses with coincident changes in chromatin structure at the beta promoter. There is a further increase in the number of transcriptionally active gamma genes and accompanying gamma gene promoter chromatin alterations. These results indicate that EKLF plays a major role in gamma- and beta-gene competition and suggest that EKLF is important in stabilizing the interaction between the Locus Control Region and the beta-globin gene. In addition, these findings provide further evidence that developmental modulation of globin gene expression within individual cells is accomplished by altering the frequency and/or duration of transcriptional periods of a gene rather than changing the rate of transcription.
|*Gene Expression Regulation, Developmental, *Genes, Switch, 0 (Chromatin), 0 (DNA-Binding Proteins), 0 (RNA, Messenger), 0 (Transcription Factors), 0 (erythroid Kruppel-like factor), 9004-22-2 (Globins), 9007-49-2 (dna), Animals, Chromatin/ultrastructure, DNA-Binding Proteins/*genetics, DNA/metabolism, Deoxyribonuclease I/metabolism, EC 126.96.36.199 (Deoxyribonuclease I), Erythropoiesis/*genetics, Globins/biosynthesis/*genetics, Heterozygote, Homozygote, Human, In Situ Hybridization, Fluorescence, Liver/embryology/metabolism, Mice, Mice, Knockout, Mice, Transgenic, Promoter Regions (Genetics), RNA, Messenger/isolation & purification, Support, Non-U.S. Gov't, Time Factors, Transcription Factors/*genetics|
|Genes & Development|
|Organisation||Erasmus MC: University Medical Center Rotterdam|
Wijgerde, M.G.J.M, Gribnau, J.H, Trimborn, T, Nuez, B, Philipsen, J.N.J, Grosveld, F.G, & Fraser, P.J. (1996). The role of EKLF in human β-globin gene competition. Genes & Development, 10, 2894–2902. Retrieved from http://hdl.handle.net/1765/2540