THE ROLE OF EKLF IN HUMAN BETA-GLOBIN GENE COMPETITION

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 b eta-globin genes in homozygous knockout mice; heterozygous mice are un affected. Here we show that EKLF knockout mice express the human epsil on and gamma-globin genes normally in embryonic red cells. However, fe tal liver erythropoiesis, which is marked by a period of gamma- and be ta-gene competition in which the genes are alternately transcribed, ex hibits an altered ratio of gamma- to beta-gene transcription. EKLF het erozygous fetal livers display a decrease in the number of transcripti onally active beta genes with a reciprocal increase in the number of t ranscriptionally active gamma genes. beta-gene transcription is absent in homozygous knockout fetuses with coincident changes in chromatin s tructure at the beta promoter. There is a further increase in the numb er of transcriptionally active gamma genes and accompanying gamma gene promoter chromatin alterations. These results indicate that EKLF play s a major role in gamma- and beta-gene competition and suggest that EK LF is important in stabilizing the interaction between the Locus Contr ol Region and the beta-globin gene. In addition, these findings provid e further evidence that developmental modulation of globin gene expres sion within individual cells is accomplished by altering the frequency and/or duration of transcriptional periods of a gene rather than chan ging the rate of transcription.