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Autonomous Silencing as Well as Competition Controls -Globin Gene Expression during Development

Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington 98195

Received 8 March 2006/ Returned for modification 6 April 2006/ Accepted 22 April 2006

To investigate the control of the -globin gene during development, we produced transgenic mice in which sequences of the ß-gene promoter were replaced by equivalent sequences of the -gene promoter in the context of a human ß-globin locus yeast artificial chromosome (ßYAC) and analyzed the effects on globin gene expression during development. Replacement of 1,077 nucleotides (nt) of the ß-gene promoter by 1,359 nt of the promoter resulted in striking inhibition of the -promoter/ß-gene expression in the adult stage of development, providing direct evidence that the expression of the gene in the adult is mainly controlled by autonomous silencing. Measurements of the expression of the promoter/ß-globin gene as well as the wild genes showed that gene competition is also involved in the control of -gene expression in the fetal stage of development. We conclude that autonomous silencing is the main mechanism controlling -gene expression in the adult, while autonomous silencing as well as competition between and ß genes contributes to the control of to ß switching during fetal development.